Week 4 Flashcards
Many of the forces affecting evolution are stochastic (random)
– Mutation
* where, when, what type
* e.g. spontaneous changes in DNA = basis for new traits like Hb -> malaria
– Recombination
* where, how much
* Natural selection -> only beneficial mutations
– Mating
* who mates and which alleles are transmitted
– Environment
* changes in conditions over time and place
* e.g. diseases/climate
Variation:
in hemoglobin
- Mutation is source of all variation
– Insertion, deletion, substitution, duplication, rearrangement - Meiosis rearranges the variation
– Recombination & independent assortment - Hemoglobin has a long evolutionary history
– Probably 500 to 1000 million years ago
– Gene duplication and divergence
– Many variations and adaptations have arisen
Evolution of the globin gene family in humans
-Humans have multiple globin genes and variations
-evolution not just in ancestors but in individual’s life stages e.g. Hb maturation
Hemoglobin mutations
- Can occur in the protein coding regions
– Alters protein sequence - e.g. HbS, HbC, HbE
- Can occur in the mRNA splicing regions
– Affects mRNA maturation and stability - e.g. beta or alpha thalassemia
- Can occur in the gene regulatory regions
– Affects mRNA production - e.g. beta or alpha thalassemia
- And, of course, the mutations can occur together in different heterozygous
combinations
HbA/HbA
reduced fitness
due to malaria
susceptibility
HbS/HbS
reduced fitness
due to RBC sickle
cell anemia
HbA/HbS
increased fitness
due to protection
against malaria
and no anemia
Hb (beta hemoglobin) allele inheritance
example with Punnett Square
25% chance of passing disease to child
Sickle cell anemia Has been called _________________________________
the first molecular disease
Clinical picture of sickle cell anemia
– Anemia, limited tolerance to physical activity, shortness of breath, jaundice,
splenomegaly, growth/development retarded, crises with agonizing pain in
joints/extremities/back/abdomen
– Capillary blockade, higher risk for ischemia/infarction/hemorrhage
– Overgrowth of bones to support erythropoiesis can produce gnathopathy
– Tissue and organ damage may develop and turn fatal
– Perhaps most worrisome in children, who have weakest vessels, still developing
* HbF (fetal hemoglobin) tends to increase in people with sickle cell anemia,
probably as a compensatory response to improve oxygen carrying capacity
since it resists aggregation and has higher affinity for oxygen (more to follow on
HbF later in the course)
sickle cell anemia first appearance
While known by oral tradition in Africa for centuries, first
written description appears in 1910 by James Herrick in
Chicago after examining a student from the West Indies
sickle cell anemia: emmel’s test
- Emmel’s test (1917) developed which shows sickling
under conditions of reduced oxygen
sickle cell anemia: inheritance
Genetic studies around 1923 state that the disease is
inherited in a dominant fashion (Huck and Taliaferro), yet
the number of cases examined is limited and more
complete studies do not take place for almost 25 years
sickle cell anemia studies
- Although it was shown in 1920s that O2
could reverse the sickling phenomenon,
later use of polarizing light microscopy (I. Sherman, 1940) provides another tool to
reveal reversibility
– Sickled cells were birefrigent - William Castle describes these properties to Linus Pauling on a train ride
- Pauling and coworkers then study hemoglobin (Hb) with newly developed tools of
electrophoresis (1940s). They find that there are two different forms and
designate the sickling-associated one HbS (see slide 20) - At the same time (1949), James Neel established the recessive nature of sickle cell
anemia. This was also independently described in another paper by E.A. Beet.
– German paper (1947) describes a methemoglobin form, HbM, and as early as 1866 it was
known that were differences in fetal vs. adult hemoglobin - Pauling’s 1949 paper is titled “Sickle Cell Anemia, a Molecular Disease”
– Principle concept of the study: protein changes and defects are tied to genes (Hb w/ electrophoresis) - In 1957, a study conducted by Vernon Ingram shows single amino acid
difference in b globin chain of HbS: glutamate to valine at amino acid
residue 6 (E6V)
– Protein fingerprinting and sequencing
– Consolidates idea of one gene = one protein - Max Perutz (with Ingram and John Kendrew) solve Hb 3D atomic-level
structure by X-ray crystallography technique
– Ingram uses HbS samples left over by Anthony Allison who was unable to obtain
3D structure results
– Perutz X-ray determined structure of Hb earns him Nobel Prize in 1962 - Additional studies eventually show that in deoxygenated state, HbS
molecules stick to each other (aggregate) and form tactoids: semicrystalline fibers that deform the RBC (these days, tactoids would
probably be called amyloid fibers)
sickle cell anemia: West Africa
- 1944 study in West Africa found sickle cell trait in ~20% of men
surveyed - Apparent rarity and uneven distribution of cases in Africa and
elsewhere was due to overlooking high rate of infant mortality
and additional contributors to health/illness/mortality - Malaria observations in relation to sickle cell anemia were first
published in 1946, and more fully investigated in the 50s,
particularly by Anthony Allison in 1954.
– Contends that HbS allele frequency is determined by trade-off
between beneficial and detrimental effects: “genetically speaking,
this is a balanced polymorphism where the heterozygote has an
advantage over either homozygote”
sickle cell anemia: thalaessemia
- Meanwhile, another story unfolds from 1920s to the 50s about another anemic condition that is named thalassemia, which is also linked to variants of Hb genes
- Cases first observed in populations near the Mediterranean (thala
- = sea)
- Initially also referred to as Cooley’s anemia, after Thomas Cooley (b-chain form)
- Decreased expression level and the amount of b-globin
- Thalassemias also identified in a-globin chains
- Cases are observed in heterozygotes (thalassemia minor) and homozygotes (thalassemia major)
- A theme develops that variation in
- sequence/structure/stability/expression adds up to a variety of subtle to drastic changes in Hb function. Disease family gets new name: hemoglobinopathies. And these manifest themselves differently under different conditions.
- Disease is a consequence of diversity
The benefit of sickle cell anemia and
thalassemia
- RBC are host cells for part of the malarial parasite (Plasmodium) life cycle
- RBC cells with HbS are poor host cells and pathogenicity is reduced
- Recently, it was shown that the HbS alters actin cytoskeleton and prevents
parasite proteins from working properly and completing life cycle - Thalassemia may reduce infectivity of RBC and increase clearance of infected
cells
ABO blood type alleles: A, B, o
A allele is codominant
B allele is codominant
O allele is recessive (null or non-functional allele)
possible genotypes: phenotypes:
AA, Ao Type A blood
BB, Bo Type B blood
AB Type AB blood
oo Type O blood
3 different I alleles
(IA, IB, i or O)
the ABO or I gene
encodes a
glycosylation enzyme
that creates
glycoproteins and
glycolipids expressed
on the surface of red
blood cells
Rh antigen
Rh antigen is determined by another set of genes and alleles. Frequency of Rh+ or people with the RBC Rh protein antigen = 80 to >99%
Blood quantum
– How much of your heritage is counted
– Often for socially-constructed categorization and resulting societal rights - typically the denial of rights, but not always
– Often described in hypodescent terms, the amount of an ‘inferior’ category
* e.g. 1/32 ‘Black’ or ‘Irish’
* one ‘drop’ could define your identity
– Negro, Aboriginal, Indian, Jew, etc.
– Indian Act (1876) of Canada categorizes many Indigenous
Peoples based on descent and degrees of descent, essentially
basing identity on blood quantum
– The Act further distinguished this descent along
sexist/patriarchal marital lines: males that marry out are
preferred over females that marry out
* Second generation cut-off rule, or non-identity with only ¼ ‘Indian Blood’
Blood purity: a concept old, abundant, and harmful
- Eugenics, selective breading ->forced sterilization,genocide
- One of the oldest declarations of this concept is
the “limpieza de sangre” or “purity of blood”
formulated in Spain in 1449 - Purpose is to exclude Muslims and Jews from
positions of power and those who converted to
Christianity (conversos and moriscos) - That is, a true Christian is one with pure blood
- Essentially you had to maintain or conserve this
status with a lineage that extended back to
grandparents or beyond - Supreme Council of the Inquisition updates the
code in 1700s to exclude those with African
ancestry - Should be evident to see how this would be shared
in Europe and then introduced to the Americas and
elsewhere with colonization episodes
– Tainting with ‘inferior’ blood, a category defined by those in power, with
‘superior’ blood
* Aryan certificate
* ‘one Jewish grandparent’ or ‘quarter Jew’
* Witches
* Christian vs. non-Christian
* Many others
– Stems from and embeds racism
– Eugenics movements
* Aim of promoting
procreation by ‘superior races’
and sterilization or elimination
of ‘inferior races’ and ‘unfit’
* ‘racial hygiene’
* fear of miscegenation
