inborn errors - pku and hemoglobin malaria

Phenylketonuria (PKU)

bodys cannot produce PAH. diets low in protein. often seek counselling regarding diet and dietary adjustments. cannot metabolize amino acid phenylalanine in proteins (meat, fish, beans).

usually -> excess phenylalanine (not required by body), gets oxidized into tyrosine (the next step in complex metabolic pathway) but usually individuals with PKU must be metabolized via a less efficient pathway -> greater risk of phenylalanine accumulation in blood that can lead to toxic accumulation leading to CNS/brain damage which can leave long term mental disability

PKU inheritance

simple inheritance. gene located at PAH locus. mutation prevents synthesis of enzyme phenylalanine hydroxylase (PAH). autosomal recessive -> wildtype will mask PKU

PKU frequencies

highest -> europeans 1/6,000 to 1/20,000 births but notable variation within Europe.

lowest -> japan, African american, Jewish groups.

high relationship between PKU & Fungus -> selection for heterozygotes (carriers) because they have a degree of resistance to the ochratoxin A (fungal toxin) of stored grain (wet). the toxin is known to bind to enzyme that manages phenylalanine contribution to protein building; protein building (development) stops. Carriers have excess but not injurious levels of phenylalanine

Tay Sachs Disease

inborn error of metabolism but not diet related. cause -> accumulation of ganglioside (a lipid sugar molecule).

body synthesizes ganglioside on an on going basis to use in cell membrane construction to a level that is unhealthy for the body.

typical -> Excess production of ganglioside gets degraded through separation of sugar molecule from lipid molecule.

Tay sachs -> unable to break down excess ganglioside which results in accumulation brain/CNS (spinal cord), nerve cells to lead to paralysis and dementia. can manifest early in life (when fast growing period when cell division rates are high)

tay sachs inheritance

mutation (95 & counting) in the HEX A gene on chromosome 15 can lead to nonfunctional beta-hexosaminidase A (HEX A), an enzyme.

is found within lysosomes (green circles, reside in the cytosol within the cell).

Selection works to favour the heterozygote (wild type/ variant allele) which maintains 'balanaced polymorphism' (keeping both alleles in population) -> historical context 15th - 19th century -> not hygenic living spaces (stressors come from environmental conditions).

Bacterial diseases common, tuberculosis, (mycobacterium tuberculosis) and thyroid fever (salmonella typhis). those who had history of TSD -> more children survived poor environment (carriers, favoured) but not homozygous TSD children. while having 2 copies is deleterious, 1 copy of each is advantageous

lysosomes

considered digestive system of cells. cell cytoplasm organelle containing digestive enzymes. breaks down/recycles cell structures, toxins and breaks down ganglioside (pulling lipid away from the sugar).

Tay Sachs has also been called 'lysosomal storage disorder' - toxic accumulation of ganglioside

Frequencies of Tay Sachs

high -> french canadians (Quebec) & Cajun (louisiana), Jewish populations (1/2,500) - 1/25 carriers.

Cystic Fibrosis

most common lethal genetic disease in European pops and pops of European ancestry.

Respiratory/ digestive difficulty due to mucus obstructions (lung and pancreatic damage).

European -> 1/500 to 1/3,800 -> carrier freq 1/20. a leading cause of death in childhood (death in infancy). avg life expectantly 24 yrs.

hypothesis -> correlation between tuberculosis and CF allele. TB -> very common,, can be protective -> heterozygous (normal allele/CF) better equipped to secrete fluid into lungs.

fluids assist with more rapid repair caused by TB. would expect evelated frq of CF allele in populations with hsitory of TB - envrionement specific

Cystic fibrosis inheritance

a number of mutations (24+) responsible for dysfunctional CFTR locus -> affects body in terms of mucus production and the ion transport across the cell membrane.

Hemoglobin Polymorphism

(malaria dependent polymorphism)

balanced polymorphism of hbahbs

malaria exerts selective pressures that selects for heterozygote (HbaHbS). Selection is relevant to time and place

4 species of protozoan parasites which cause malaria

plasmodium -> vivax, ovale, malariae, falciparum ( the most deadly).

differ in terms in risk they present and lethality. more deadly disease is, the more it can impact and shape genetics and futhers selectie potential

P.vivax

globally, most frequent and widely distributed malara parasite -> less fatal

P. falciparium

most recent variant and most fatal. children are most susceptible to dying in endemic areas in the tropics. responsible for 1-3 mil deaths per year are most common in africa and 25% of infant deaths. can be transmitted by around 30 species of mosquito. 80% of RBCs can be infected

parasite & RBCs

parasite matures in the hosts RBCS, feeding on the hemoglobin and multiplying until maturity and break out of RBCS and waste and fever.

treatment goals are to prevent the binding and invasion of parasites in the RBCs.

two components -> erthrocyte binding antigen 175 (protein on the surface of parasite) & glycophorin (on the red blood cell). They bind together and trigger further pathways within RBC. parasites use part of the RBC membrane to create their compartment within RBC -> membrane acts as a conduit to RBC surface

inside the RBC

parasites synthesize proteins that -> 1. increase adhesive properties of RBC 2. create protrusions on RBC surface.

both anchor RBC in capillaries & prevent 'damaged' RBC (recognized by the body) from being sent along to spleen for destruction

symptoms in malaria

anemia**, high fever and chills, vomititng/diarrhea. headaches, nausea. fatigue

Anemia

can be identified with below normal levels of hemoglobin or hematocrit. for hemoglobin <12g/dl non pregnant woman & <13 g/dl men (grams hemoglobin/decilitier of blood).

reductions in Hbs may compromise important function. Result of biology + environment, others are only genetic (sickle cell)

hematocrit

proportion of RBCS in a sample

Red blood cells

carry oxygen from the lungs (absorb O2 via tiny alveoli in the lungs) -> is delivered via arteries and capillaries, to organs, tissues, everything.

they carry CO2 back to the lungs via veins and release CO2 to be expelled with every exhale. a trip is around 30-45 seconds and are programmed by stem cells in bone marrow and last about 120 days.

Contain a metalloprotein hemoglobin (Hb = iron + protein

blackwater fever

dark urine. because parasite destroys RBCS -> frees hemoglobin in blood plasma (hemoglobinemia).

Hb is then filtered through the kidneys, damaging it, and leaking of hemoglobin in to the urine (hemoglobinuria)

hemoglobin structure

consists of 4 polypeptide chains & heme unit.

2 alpha chains -> 141 amino acids (gene on chromosome 16).

2 beta chains -> 146 amino acids (gene on chromosome 11).

2 varients - typical hemoglobin (HbA) and variant hemoglobin (HbS)

hemoglobin structure

heme unit - sites for binding 4 oxygen molecules. when bound with oxygen, they red, without they bluwish

anemia of chronic disease

the body handles iron conservativly. if iron is not bound in hemoglobin, the iron will try to store the free iron and push itself into anemia under certain conditions ( infection)

Iron Deficiency

inadequate iron in the body (needed to form hemoglobin). lack of energy, pica, headaches.

very hard at heart to beat at accelerated pace. body can become depleted via blood loss, inadequate diet, body changes, inadequite absorptions of GI

eggs and iron

most iron in eggs is bound to phosvitin that lowers the bioavaliablity of iron. when bacteria breaks into they look for iron but the whites is low in iron. and idk tea can drive someone into amenia the tanents in tea

dietary niches

will differ, heavy meat eating population might be less effected from tea/coffee drinking

Ireland

strong tea culture. but also had higher frequency (10-11%) if the HFE gene varient C282Y allele associated with hereditary hemochromomatosis (higher iron absorption and storage) -> too much iron "celtic curse".

ireland is an island (dynamics of gene flow and random genetic drift). drift enhanced by population loss (colonialism, famine, migration).

mutation was the force that created the gene but gene flow took varient and moved it x. under envrionemental circumstances, NS selected for C282Y because body needs iron during famine.

C282Y

iron is not stored in macrophages but exported to parechmyal cells (bloodstream - risk plague, anthrax, cholera) - allows diseases that look for iron in bloodstream to have advantage.

having this would give advatnge. even after famine, new diet of wheat (celiac/dietary malapsorption) and tea (iron-absorption blocking tannis) - counters balance risk of tea

colonialisms impact on a population

decline and malnutriotn shaped stressors that favoured mutation random varient of C282Y