Exam 3 Genetics
ApoE alleles - how does inheritance and expression work
ApoE2 = good ApoE3 = neutral ApoE4 = bad - get an allele from both mom & dad and they sum, for example - someone gets 2 & 4 = they are neutral (believed to be both genetic & environmental... multifactorial)
Genetic risk factor for AD
ApoE4 allele is the main risk factor - ApoE is a major component of VLDL, is a transporter of lipids in the brain as well as amyloid beta... ApoE4 = reduced lipid carying capacity & thus impairs clearance of amyloid beta (causes build up/plaque)
Autograft Isograft Allograft Xenograft
Auto - From one person to oneself Iso - From identical twin (monozygotic twins) Allo - Members of same species Xeno - From another species
Rhematoid Arthritis (RA)
Autoimmune disease effecting synovial joints (moving joints) - Increase rheumatoid factor - Can become systemic: inflamed blood vessels & organs
Cellular IDD
Block in differentiation & development of T cells = increased susceptibility to intracellular microbes = increased # of malignant tumors (cancer) = death in early age
Severe Combined Immunodeficiency (SCID) - Survival? - Issue with this - Treatment
Both limbs of lymphocyte system (T cell & B cell/Cellular & Humoral) are deficient... - Cannot survive with this - Lack Helper T cells = B cells do not get the help they need - Bone marrow transplant to get more T cells
Prader-Willi Syndrome
Caused by a lack of genetic material in the 15 pair of chromosomes. - Paternal deletion (70%) with maternal imprinting... so the gene is usually inherited from the father, but since it is deleted, they have no gene to express and thus express the disease. - Two maternal copies of gene (25%), so no active copies of the gene - <5% imprinting defects The leading genetic cause of obesity. As well as intellectual impairment
Angelman Syndrome (AS)
Caused by a lack of genetic material in the 15 pair of chromosomes. (particularly lack UBE3A) - Maternal deletion (68%) with paternal imprinting... so the gene is usually inherited from the mother, but since it is deleted, they have no gene to express and thus express the disease. - UBE3A mutation (11%)... UBE3A is a gene in the brain - Two paternal copies (7%), so no active copies & because of this, they lack UBE3A in the brain - 3% imprinting defects
Variation in number of variable number tandem repeats (VNTR)
Class 1 = risk... Class 3 = protective... More VNTR = more protection
APC - examples
Complexed with MHC molecules (plate that antigen is served on) - Dendritic cells (professionals), Macrophages, & B-cells
Erythrocytes (blood cells) have few markers that act as antigens
- ABO antigen - Rh antigen factor
Two hypotheses for cause of AD - Cholinergic - Misfolded & aggregated preteins amyloid & tau
- AD begins as a deficiency in acetylcholine production - Beta amyloid deposits are the causative factor of the disease
Genes associated with early onset AD
- APP gene: chromosome 21, 25+ different missense mutations identified (allelic heterogeneity)... Mutations disrupt normal cleavage of APP and this causes accumulation of plaques & tangles - PSEN1 gene: component of gamma secretase, 150+ different mutations, gain of function mutations that yield abnormal PSEN1, which affects cleavage of APP. Bad cleavage of APP causes accumulation of plaques & tangles - PSEN2 gene: involved in APP processing and degradation, 11 different mutations
T-cell receptors
- Have a specific antigen binding site that differs from one T cell clone to another - T cell receptors cannot combine with antigen unless the antigen is complexed with bodies own proteins... need APC
Helper T cells Cytotoxic T cells
- Helper T cells help all other cells... ex- help B cell become a plasma cell - Cytotoxic T cells yield Perforin and Granzyme -- Perforin = punches hole in cell to get granzyme in -- Granzyme = apoptosis of the infected cell
Chronic Granulomatous Disease (CGD)
- Lack of *NADPH oxidase activity* --> lack phagocytes - Neutrophil # is fine, but function is bad = see bacteria # rise - X linked recessive & AR
Diabetes Mellitus - what type of inheritance - 4 types - what is the disease characteristics
- Multifactorial inheritance - Type 1, Type 2, Gestational, & MODY - Disease characterized by high levels of blood glucose, resulting from deficits in insulin production, insulin action, or both
Skin color - what type of inheritance
- Multifactorial inheritance - genetics = type of skin pigments - environment = sun exposure, physiological issues/conditions, & circulation of blood near skins surface
# of MHC on given cells - RBC - Hepatocyte - APC
- RBC = 0 (unnucleated) - Hepatocyte = class I only... 6 total on the surface of the cell (3 from mom, three from dad) - APC = class II only... 6 total on the surface of the cell (3 from mom, three from dad)
Secondary Immunodeficiency Diseases caused by
- Radiation, Infection, Drugs, & Pathogens
Why do specific HLA's increase risk for autoimmune disease? Why do HLA's in general predispose to autoimmune disease?
- Some are not as good at presenting "self" -
Graft rejection reaction - Graft vs Host disease -
- T cell from recipient attacks donors tissue (solid organ) - T cell from donor attacks hosts tissue (bone marrow)
During the 5th week of prenatal development, all embryos develop 2 sets of... - -
- Unspecialized gonads - Reproductive ducts: (Mullerian = female specific & Wolffian = male specific)
Autoimmunity may arise in several ways
- Viruses use host proteins on the viral cell surface, these proteins become targets of the immune system - Thymocytes that recognize "self" antigens survive rather than self-destructing - Deposition of immune complexes -Autoantibodies recognize "self"proteins - Molecular mimicry = non-self antigen may coincidentally resemble "self" antigens
DiGeorge Syndrome
-Congenital absence of the thymus gland = T cell deficient = vulnerable to viral, fungal, and bacterial infections -Micro deletion of chromosome 22, multiple systematic problems... AD
What delays AIDS
Genetic variants of CCR5... - if have CCR5 variants that do not let you express CCR5, you can have the HIV virus but will never get sick/AIDS
Genetic factor predisposing to autoimmune diseases
HLA's - MHC Class 1 (A,B,C) - MHC Class 2 (D__)
2 ways B-cells kill bacteria
Neutralize - bind to the bacteria & do not allow it to bind to the cell surface Opsonization - flags bacteria for neutrophils to come destroy it via phagocytosis
Y-linked inheritance
Only males have Y chromosomes, passed from fathers to sons, all Y-linked traits are expressed
2 theories for ALS
Oxidative Stress - increased markers of oxidative damage, increased ROS, copper chelators increase mice survival Protein Aggregates - aggregates correlate to disease progression, immunoreactive for mutant SOD1... unclear if aggregates harmful or protective
X-linked recessive
Pattern of genetic transmission - affects mostly Males, has no M-to-M transmission, mother is usually an unaffected carrier
X-linked dominant
Pattern of genetic transmission - both M and F affected; no M-to-M transmission; affected father passes trait to all daughters, every generation (more common in females); affected mother passes trait to both sons and daughters; a single mutant allele can produce the disease.
Antibodies must have enough antigen-binding diversity to recognize every possible pathogen encountered... how do they get this diversity?
Prior to antigen exposure, there is random splicing together of different gene segments during B cell development - VDJ recombination = cut and paste via chromatin remodeling
Recombination activating genes
RAG-1 & RAG-2 - make DNA breaks for recombination activation (for diversity of immune system)
Red, green, blue wavelength
Red = longest Green = medium Blue = shortest
Humoral IDD - Example
Reduced # of peripheral B cells = increased susceptibility to pathogens (virus, bacteria, or both) - Brutons syndrome
Rods - Cones -
rods- black and white cones- color
SRY gene
sex determining region of the Y chromosome - encodes a transcription factor protein that leads to the development of testes (testes secrete anti-mullerian hormone to destroy female structures and testosterone & DHT to develop male structures)
Liability distribution
the manner in which the chances of developing a multifactorial (genetics + environment) disease is distributed in a population; as number of genetic and/ or environmental risk factors increase, chance of developing disease increases
Emperic risk
the probability that a trait will occur or recur in a family based solely on experience rather than on knowledge of the causative mechanism
MHC
this is a protein that help display antigen to T cells or B cells, and also helps IS to recognize self vs non-self
Sex-influenced traits - male pattern baldness
traits controlled by autosomal genes that are usually dominant in one sex but recessive in the other sex... - male pattern baldness is inherited, but males express it while females do not because the expression is influenced by # of androgens, # of androgen receptors, & age
MHC molecules are the basis for ________
transplant rejection/acceptance - need 6 to match for transplant
T cell receptor (TCR) diversity
Similar to B-cell antibody diversity! Both have multiple germline copies (VDJ), and go through random splicing together... both RAG1 & RAG2 with B cells and T cell used for recombination
Hemophila - causes
a condition that impairs the bloods ability to clot - Lack of Hemophilia A (more common) or Hemophilia B
Gestational diabetes
a form of diabetes mellitus that occurs during some pregnancies - increased risk for mother to have type 2 diabetes & increased risk for child to have childhood obesity (type 2)
Gene imprinting
a phenomenon in which gene expression and phenotype depend on which parent the genes come from/aren't silenced - Reversible! not a mutation, but rather an epigenetics example (often hypermethelyated)
Alzheimer's disease - Neuropathology - Affected area - Proteins
a progressive and irreversible brain disorder characterized by gradual deterioration of memory, reasoning, language, and, finally, physical functioning - loss of neurons and synapses... - cerebral cortex (temporal - memory, parietal - language, frontal - behavior) - Protein misfolding disease
T cells are born in the _______ & mature in the ________
born in the bone marrow, & mature in the thalamus... once developed they hang out in the bone marrow looking for specific antigens
MHCs (basically same as HLAs) are important why?
correlation between specific MHC alleles & disease development
Phenotypic Sex
development of external reproductive structures
2 threshold diseases
different threshold for disease as different sex's have different probabilities of being affected
DHT
dihydrotestosterone develops prostate and male external genitalia important for stimulating the development of these male external ganglia along with testosterone
Type 1 diabetes - age - genetic association
disorder in which the pancreas cannot produce enough insulin... due to beta cells of pancreas being destroyed - younger onset - associated with HLA class II alleles, which are associated with MHC proteins (autoimmune disease)... even if have susceptibility gene, need environmental trigger which is Coxsackie B4 virus
Class 1 MHC
found on almost all nucleated cells of the body - Cytotoxic T cell recognition (CD8+)
Genome Wide Association Studies (GWAS) - looks for what to identify similarities? - Pro's
genetic method in which researchers scan the entire genome of individuals who are not related to find the associated genetic variations with a particular disease - seek correlation between SNP patterns & phenotypes - narrows down likely candidates & don't need pedigree
Atpoic
genetic susceptibility to an allergen
Type 2 diabetes - risk factors - age
lack of insulin production (beta cells work, but are dysfunctional Main issue is resistant cells block insulin receptors and this lack of insulin sensitivity tells our body that our cells are hungry, so we overproduce glucose - Visceral abdominal fat - risk increases with age Environment and genetics both effect the epigenome for phenotype of type 2 diabetes
MHC
main risk factors for all autoimmune diseases... rejection comes from these
Severity of disease in parents and recurrence risk in children
more sever the parents disease is, more traits they have for the gene (both environmental and genetic), & the more traits they have, the more they can pass on to children --> more severe phenotype = higher recurrence risk - # of effected individuals, did not increase recurrence risk in Mendelian traits, but it does in multifactorial traits
Addison's disease
occurs when the adrenal glands do not produce enough of the hormones cortisol or aldosterone - High melanin, glucose, & potassium... Low sodium & BP - Weakness & Weight loss
Class 2 MHC
on the surface of antigen-presenting cells (APCs), including B cells - Helper T cell recognition (CD4+)
X-inactivation
one of two X chromosomes is randomly inactivated and remains coiled as a Barr body... leaving only 1 X chromosome to be expressed - random, with the exception of paternally derived X chromosomes inactivated in cells that will become extraembryonic tissue - X inactivation permanent in somatic cells but not germline cells - abnormal X-chromosome is preferably inactivated, leaving the normal active
Gonadal sex
ovaries or testes (initiated by gene expression pathways)
Filaggrin
protein that binds the cytoskeletal keratin filaments together into coarse, tough bundles to keep allergens out. When someone has atopic dermatitis, they have less Filaggrin and thus the allergens get into their skin and cause inflammation/rash
Androgen insensitivity syndrome (AIS)
A condition in which the testicles (undescended) secrete normal amounts of testosterone during male embryonic development, but the tissues do not respond to it. As a result, a clitoris, labia, and a short vagina develop, but the internal female structures do not develop because the testicles (undescended) still secrete Mullerian duct-inhibitory substances. - Female gender identity, but no menstruation
Duchenne muscular dystrophy - cause - females?
A human genetic disease caused by a sex-linked recessive allele on the X chromosome... DMD gene in particular; characterized by progressive weakening and a loss of muscle tissue - majority (~70%) frameshift mutations leading to absence of dystrophin (DMD) (30% del novo mutations) - since it is X linked recessive, females express a less severe phenotype (unless also have turners syndrome)
5 alpha reductase deficiency
Absence of DHT - AR, affects males; have testosterone, but lack DHT; ambiguous genitalia until puberty (so raised as girls, then testes drop and penis develops); testosterone and estrogen levels are NORMAL
Congenital Adrenal Hyperplasia (CAH) - Gene responsible - Three manifestations
Condition during prenatal development in which the adrenal glands produce high levels of androgens; sometimes associated with masculinization of external genitalia in genetic females; or early puberty in males - CYP21 gene mutation - 1. Virilization: females develops male with male sex characteristics... 25% 2. Salt-wasting forum: unable to make aldosterone (males more at risk because born normal so doctors do not look for it early)... 75% 3. Non-classical (late onset): androgens excess in later life... rarely occurs
Testes secrete Mullerian inhibitory factors that ______________
Degrade female parts (uterus & ovaries)
Beta-amalyoid plaques (as a cause for AD) - how cause AD
Dense deposits of proteins in extracellular space - APP is precursor, improper Beta cleaving of APP leads to unsoluble products that come together to form plaques
Hemophilia A
F8 gene on X chromosome... inversion mutations of exons 1-22 disrupts then entire F8 gene and causes Hemophila - Factor VIII deficiency
Hemophilia B
F9 gene on X chromosome... 3,000 different mutations, majority missence is the cause of Hemophilia here - Factor IX deficiency
Immunodeficiency diseases (IDD) - Primary vs Secondary - Humoral vs Cellular IDD
Failure to produce one or more components of the immune system... mostly characterized by infection - Primary = inherited genetic defect - Secondary = secondary to something else (ex- secondary to radiation) Can be B cell or T cell deficiencies - Humoral = B cell - Cellular = T cell
MHC's with immune system diversity - Three groups -- inheritance paterns
Haplotype- particular combination of MHC's found on one parental chromosome... inherited together (from a single parent) On chromosome 6 - Class I: all nucleated cells, 3 types... HLA-A, HLA-B, HLA-C... (recognize A,B,C) - Class II: found on APC's, HLA-DP, HLA-DQ, HLA-DR... (recognize all D___) - Class III: MHC alleles show codominance... both haplotypes are expressed in an individual... children will never have the same MHC allele combination as one of their parents, but will always have half of each parents
Types of graft rejection reaction - Hyperacute - Acute - Chronic
Hyperacute - On operating table Acute - Within days/months Chronic - 5 months to years
Neurofibrillary tangles
Hyperphosphorylated tau proteins... found within AD neurons... Tau proteins hold together the microtubules, as they degrade, microtubules fall apart and Tau proteins clump together forming neurofibrillary tangles
Allergic response _______ antibodies are made and bind to _________ ___________
IgE antibodies are made and bind to mast cells Allergens bind to mast cells on IgE receptors, and mast cells release allergy mediators
5 types of antibodies on constant region
Igm = the first produced... then switch to IgG, IgA, or IgE IgG = the best... crosses placenta & has most functions IgE = associated with allergic reactions IgA = found in lumen of tracts IgD = as a B cell receptor
Innate vs Adaptive
Innate: fast (24-48 hours), macrophages, neutrophils, etc. (anything not T or B cells), same response to all foreign bacteria/cells Adaptive: slower (7-10 days), T-cells & B-cells, specific responses to different types of bacteria/cells
The Multifactorial Model (multifactorial inheritance)
Loci act in an additive fashion, each adding or detracting a small amount from the phenotype - produce a continuously varying phenotype (ex- hypertension = lot of variation, can have it then not) There is no dominance or recessivity at each loci
Maturity Onset Diabetes of the Young (MODY) - penetrance - B cell function
Monogenetic (single gene mutation) - AD - 40-90% penetrance - More B cell function than type 1, but less than type 2
ALS
Most common motor neuron disease - LOD score of 5.03 @ 10 centimorgans - Sporadic (90%) or Familial (10%)... earlier onset for inherited/familial - gene 21 - SOD1 shows linkage - SOD1 mutations are gain of function mutations
HIV - Infected cells - Receptors involved
Most known Human Immunodeficiency virus - Infects macrophages & Helper T cells - Need 2 receptors --> CD4+ & CCR5 or CXCR4
Brutons Syndrome (XLA)
Mutation in B cell tyrosine kinase (BTK) = lack of maturation of B cells - Higher incidence of bacterial infections and reduced efficiency of vaccines (because lack mature B cells)
Do B cells make antibodies?
NO! B-cells differentiate into plasma cells and memory cells, and plasma cells secrete antibodies
Inactive immunity Active immunity
Someone gives you antibodies You create your own antibodies and memory cells
ABO antigens
Specific small carbohydrates found on erythrocytes - A&B are different versions of complete carbohydrate - O is an incomplete carbohydrate
Maternal imprinting
The expression of a gene only when inherited from the father, because the copy of the gene inherited from the mother is inactive due to methylation in the course of gamete formation.
Paternal imprinting
The expression of a gene only when inherited from the mother, because the allele of the gene inherited from the father is inactive due to methylation in the course of gamete formation.
Sex ratio - Primary - Secondary - Tertiary
The number of males per 100 females in the population... #males/#females x100 - Primary = at fertilization - Secondary = at birth - Tertiary = at maturity
Heritability - Range of value - Higher the value = - Equation
The proportion of variation among individuals that we can attribute to genes. The heritability of a trait may vary, depending on the range of populations and environments studied.It is an estimate value, not a direct measure - Ranges from 0-1 - Higher the value (closer to 1), the greater the genetic component - 2 x (MZ concordance - DZ concordance) -- Concordance = % of pairs of twins in which both twins express the trait
Adenosine deaminase deficiency (ADA)
Type of SCID, Genetic, AR - X linked - Defects in T cells, B cells, & NK cells = lack of response to many receptors = lymphocyte death
When would a vaccine not help with humoral immunity
When they generate T cells
Color blindness - most common type - mutation location
X-linked recessive (mostly effects men) - Dichromacy: only see two types of cones... cannot see one of red or green - Mutations of color blindness are in a number of genes... a gene in either the opsin, or the chromophore itself
Embryo develops into male or female based upon the absence or presence of _____
Y gene... in particular the SRY region of the Y gene... when SRY is present, the person develops testes (if not present they do not develop testes). Testes secrete masculine hormones, with testicular hormones present, male external sex characteristics are developed. (with no testes present, no androgens are secreted and thus female external ganglia develop
Is there high genetic susceptibility with hypersensitivity/allergies?
YES! (but it is multifactorial & requires environmental factor)
Allergy
abnormal Hypersensitivity acquired by exposure to an antigen
Class II MHC = most ___________ _____________
autoimmune diseases
Autoimmunity - Prevalence -Examples
pertaining to one's immune system attacking its own tissues or cells - more prevalent in women - Type 1 Diabetes (local) & Systemic Lupus Erythematosus (systemic)
