(Midterm 2 half) Topic 4: Understanding Genotype/Phenotype Interactions

Haemoglobin

Major component of red blood cells— responsible for transporting oxygen in the blood to the tissues and returning CO₂ to the lungs

2 alpha chains, 2 beta chains, heme cofactor, carries iron which can bind oxygen

Haemoglobin is a heterotetramer of ______ and ____ and each chain is associated with ______ which _______

tandem gene duplications, LCR

Due to _____ in ancestral sequences the haemoglobin locus has several coding regions controlled by a ______

spatial (tissue specific), temporal (time-dependent)

LCRs exert ____ and ____ control

a1 and a2, no amino acid differences, epsilon and gamma and delta and beta, up to 39 amino acid differences

The alpha globin cluster contains ______ which have ______; the beta globin cluster contains _____ which have ________

alpha and gamma Hb, birth, alpha and beta Hb

Fetal Hb is made of ______ and switches to adult Hb at ______ which is made of ______

Alpha, partial pressure of oxygen in the air, alpha/beta, alpha/gamma

___ Hb does not show temporal regulation. At birth ________ triggers the genetic switch to adult haemoglobin (HbA)— in adults 98% of haemoglobin is _____ and 2% is _____

Thalassemia

Caused by mutations in the coding regions of the globin loci that can decrease the synthesis of either alpha or beta haemoglobin

Alpha Thalassemia

Decreased alpha globin synthesis sometimes due to a point mutation in a1 or a2

deletion of 1 or more coding regions, NAHR, a1, gamma

80-85% of cases of alpha thalassemia are caused by ______ due to _____ most often between ___ and ___

form homotetramers, gamma tetramer, Hb Bart’s, beta tetramer, HbH

If there is not enough alpha globins the excess gamma and beta globins ______. In the fetus, this means _____, which is referred to as _____. In the adult, this means _____, which is referred to as _____

anemia, dizziness, cramps, shortness of breath, and jaundice

Alpha thalassemia symptoms include:

Beta Thalassemia

Decreased beta globin synthesis sometimes due to point mutations in HbB

excess alpha globin, damage to plasma membrane, toxic protein aggregates, normal phenotype, beta thalassemia minor, beta thalassemia major

90% of cases of beta thalassemia are due to ______. Insufficient beta globin causes ______ which causes ____ and ____. 2 functional beta globin genes = ____, 1 functional beta globin gene = _____, and 0 functional beta globin genes = _____

anemia, jaundice, heart issues, kidney problems, and bone abnormalities

Beta thalassemia symptoms include:

inability to turn over iodine

The yellow colouring of jaundice is caused by…

Complex Thalassemia

Thalassemias caused by deletions in the locus control region

Hereditary Persistant Fetal Haemoglobin

Caused by deletions that remove the haemoglobin delta and beta coding regions but the locus control region remains intact

HbF

Heterozygouse HPFH have 20-30% _____

Hb binds more tightly therefore oxygen is not offloaded to tissues as well but this does not typically result in any clinical presentations

Symptoms of HPFH include:

loosens the interactions between histones and DNA by neutralizing the positive charge on histones therefore weakening the ionic association between the DNA backbone and nucleosome

Addition of acetyl groups to histone lysine residues…

H3 and H4 acetylation

_____ in the haemoglobin LCR is associated with beta globin expression

Imprinting

One copy of a gene in an individual is expressed while the other is suppressed due to epigenetic differences that are dependent on the parent of origin

methylated, maternally imprinted, paternally imprinted, imprintining is reset through the germline

During gametogenesis DNA is differentially _____— ~80 regions are _____ while ~3 regions are ____ therefore _____

imprinting control regions, cis regulation of alleles

Imprinting methylation occurs at ______ within imprinted gene clusters which allows for _______

Prader-Willi Syndrome

Caused by loss of paternal gene expression on chromosome 15 that can occur due to deletion of the paternal copy, maternal uniparental disomy, or imprinting defects

Angelman Syndrome

Caused by loss of maternal gene expression on chromosome 15 that can occur due to deletion of the maternal copy or paternal uniparental disomy leading to UBE3A deficiency

SNRPN, possibly involved in tissue-specific alternative splicing, necdin, regulator of neural interactions

PWS and AS are caused y deletions of 15q12 affecting the ____ (__________) and ___ (_________) genes

paternal, maternal

PWS happens when the deletion lies on the ____ chromosome but the _____ chromosome is inactivated

obesity, short stature, obsessive eating, small hands/feet, mild intellectual disability

Prader-Willi syndrome symptoms include:

severe intellectual disability, happy and affectionate

Angelman syndrome symptoms include:

Uniparental Disomy

An individual carries two copies of a chromosome from one parent

Non-disjunction and aneuploidy (n-1), non-disjunction and aneuploidy (n+1), both chromosomes with deletions inherited

_____ in the paternal lineage and _____ in the maternal lineage = Prader-Willi by UPD. _____ from the paternal lineage = Angelman by UPD.