Exam 3 Genetics

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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)


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