Slide Decks 1-5 Flashcards
(93 cards)
1
Q
What is malaria?
A
A protozoan parasite of the genus Plasmodium that lives within red blood cells
2
Q
Who has the survival advantage if infected with malaria?
A
Individuals who are
heterozygous for the sickle cell
mutation
3
Q
True or False: Social factors influence
human genetic diversity and our knowledge of it
A
True
4
Q
What is the goal of scientific literature?
A
To make a convincing case to its audience (readers or listeners) that the writer is asking an important or at least interesting question, and has found a possible answer to that question.
5
Q
Define Primary Literature
A
Articles that describe new studies
Scientists write primary research articles to outline, summarize, and share the details of their own experimental studies.
6
Q
Define secondary or review literature
A
Articles/books/book chapters that summarize what others have written or done without doing new studies
7
Q
What is a benefit of secondary or review literature?
A
Review articles/ book
chapters summarize primary literature and help readers gain
a broader understanding of a topic or field. Review articles also can lay out the evidence on each side of a controversial field, or competing theories about how a process works
8
Q
Describe the layout of scientific literature
A
- Introduction: It can be their own question, a problem that many scientists working in the field know about, or an observation that the current understanding within the field cannot explain. The context for thinking about the question, usually by describing (and citing) what others have seen and said.
- Materials and Methods: If the study is new, the authors will describe how they conducted the research. If its a review article, the author may. describe the scope of what the rest of the article will talk about.
- Evidence to support claims: The evidence can be the data the author collected from a series of experiments, a logically reasoned argument, something that someone else published in the past, or some
other trustworthy source of information. This is when the writer actually tries to show they have found a possible answer to the original question. It also is when a
good writer will outline the potential limitations of their own argument, and lay out new questions to think about.
9
Q
How should you begin to read a scientific paper?
A
Look at how its structured
10
Q
How could someone new to the field read an article strategically if they want to Increase your background knowledge?
A
Focus on introduction
11
Q
How could someone new to the field read an article strategically if they want to see examples of overall experimental designs related to their own questions
A
Focus on methods
12
Q
How could someone new to the field read an article strategically if they want to find out which statistics tests are used to analyze a particular type of data?
A
Focus on the Statistics section, which tends to be the last part of the Methods.
13
Q
How could someone new to the field read an article strategically if they want to see how particular types of data are summarized and displayed?
A
Focus on the graphs, tables, and figures in the Results
14
Q
How could someone new to the field read an article strategically if they want to learn how data and evidence from studies by others has been interpreted?
A
Focus on the interpretations in the Discussion.
15
Q
How could someone with experience in the field read an article strategically if they want to get a deep understanding of a particular
question that interests them?
A
Focus on how the story told by the Introduction is organized, &
what prior knowledge is emphasized.
16
Q
How could someone with experience in the field read an article strategically if they want to find out where other professionals are
getting reagents or study organisms?
A
Focus on the list of sources, or where the authors say they got
materials.
17
Q
How could someone with experience in the field read an article strategically if they want to identify & understand controversies or
unanswered questions?
A
Focus on differences in stories told in the Discussion section by
authors from different labs.
18
Q
How could someone with experience in the field read an article strategically if they want to put their own study into a larger context?
A
Focus on the narrative in the Discussion. What do other authors
say is important? Why?
19
Q
How could someone with experience in the field read an article strategically if they want to compare their results to what others have
reported?
A
Focus on the data tables and figures, particularly how the trends
they observed compare to published work by others
20
Q
How could someone with experience in the field read an article strategically if they want to find additional articles that could be useful for interpreting their own work?
A
Focus on the full list of Literature Cited.
21
Q
How could someone with experience in the field read an article strategically if they want to know what the influential labs, authors, and papers in the field are?
A
Focus on which papers and authors are listed in the Literature
Cited; which authors show up repeatedly.
22
Q
Describe the range of disease severity in malaria
A
- Asymptomatic: no symptoms
- Clinical uncomplicated: fever, headache, vomiting, and diarrhea.
- Severe malaria: severe anemia, pulmonary or renal dysfunction,
neurologic changes.
23
Q
Which type of malaria are most likely to progress to severe?
A
P. falciparum and P. knowlesi are the most likely to progress to
severe, fatal disease and deaths are often due to central nervous
system involvement (cerebral malaria), acute renal failure, severe
anemia, or acute respiratory distress syndrome
24
Q
What types of malaria cause morbidity but are less likely to
cause deaths?
A
P. vivax
P. malariae
P. ovale
25
What are the factors that affect disease severity?
1. Immune status
- innate response
- adaptive response
2. Parasite strain
- parasite replication rate
- parasite sexual conversion rate
3. Host genetics
- RBC permissiveness to parasites
- Metabolic differences
26
Describe the different species of plasmodium:
1. Plasmodium falciparum
* Causes the majority of malaria
deaths worldwide
* Most prevalent in sub-Saharan
Africa
2. Plasmodium vivax
* Second most prevalent species
* Prevalent in Southeast Asia and
South America
* Dormant liver stages (which can
reactivate years later)
3. Plasmodium ovale
* Less prevalent
* Dormant liver stages (which can
reactivate years later)
4. Plasmodium malariae
* Less prevalent
5. Plasmodium knowlesi
* Thought to only infect non-
human primates (macaques)
* Has been clearly demonstrated
to infect humans
* Can cause lethal infection
* Zoonotic transmission
* Mostly in Malaysia
27
Give the stats about Plasmodium falciparum
- Est. 241 million cases of malaria worldwide in 2020
- Est. 627,000 deaths from malaria in 2020
- 95% of cases in Africa, 2% in South-East Asia
28
Give the Plasmodium falciparum asymptomatic and severe symptoms
Asymptomatic Uncomplicated
- Fever
- Flu-like symptoms
Severe
- Anemia
- Seizures and coma
- Death
29
What can p. Vivax parasites form?
Hypnozoites,
which stay dormant in the liver for long periods of time. When they become active, it is called a relapse.
Relapses are known to occur up to 8 years after primary infection
30
What makes a malaria parasite invade a RBC
Duffy blood groups on surface.
Plasmodium parasites can only
invade cells that have a receptor
that they can bind to.
For P. falciparum, there are
additional receptors including
Rh5/Basigin and CD55 as well as
some glycophorins.
For P. vivax, this RBC receptor is
called duffy.
Duffy negativity is prevalent in
West Africa and among
descendants
31
What is Fst?
A measure of genetic differentiation between populations. Is the difference within them greater than the difference between them?
32
What does an Fst of 0 mean? of 1?
When FST = 0
There is not any significant difference in the variation within population 1 versus the variation within population 2 with respect to the alleles A & B of gene X. Natural selection is not apparent at this locus.
When FST = 1
The two populations have a significant difference in the number of alleles A & B of gene X. Population 1 has 100% A allele, whereas population 2 has 100% B alleles. Natural selection appears to be occurring at this locus (and fixation has been reached).
33
What is evolutionary time? What are some of the categories we have split time up into?
Earth’s history can be organized into
specific time periods based on geology
* Pleistocene – Earth’s most recent
glacial period. Period in which the
Homo genus originated in Africa and
spread, leading to a distribution of
modern humans across the world
* Holocene – the current phase we are living in right now. After the last glacial period & characterized by the rapid population growth of Homo sapiens.
* “Anthropocene” – unofficial term for
the phase of time characterized by the consequences of human activity
34
How is the concept of evolutionary time relevant to this course?
Understanding when an event occurred in evolutionary
time can allow us to understand what evolutionary pressures may have been acting on humans at that time.
35
What is a gene?
The basic unit of inheritance
(genes are passed from parents to
offspring); a packet of information for
coding a protein.
A gene can be anywhere from a few
hundred to several thousand base pairs
* Humans have approximately
20,000 genes
36
What is evolution?
A process by which organisms change over time
* At the heart of evolution is mutation
* Mutations produce genetic variation
37
What is a mutation?
A change in the DNA sequence
* Results from DNA copying
mistakes made by polymerases
(during cell division), or exposure
to mutagenic agents like radiation
38
Explain germ-line vs. Somatic mutations
- Germ-line mutations occur in the eggs and sperm and are passed onto offspring (evolution can act on these)
- Somatic mutations occur in the body but are not passed on (evolution cannot act on these)
39
Explain frame shift vs point mutation
Frame-shift mutations result in a change in multiple bases
-Deletion
-Insertion
Point mutations result in a change in a single base
-Substitution
40
What are the different types of point mutations?
- Missense: encodes for a different amino acid
- Nonsense: Encodes a stop codon
- Silent: New codon codes for the same amino acid (wobble position)
41
What is fitness?
The environment serves as a selective
force which selects those individuals
that are best adapted to their
environment (because the best
adapted individuals leave more
offspring in the next generation)
42
What is a population?
A group of organisms that live in the same habitat and are reproductively compatible with one another (part of the same mating pool)
* A human population is a group of
humans (Homo sapiens) living
over many generations in the
same habitat
43
True or False: Genetic evolution in human populations is a property of the group, not the individual
True.
(individuals can respond/react to their environment, but populations can evolve to adapt to their environment)
44
What affects whether a red blood
cell has the duffy antigen or not on its surface
A particular SNP at the
duffy gene promoter
45
What is an allele?
Humans have around 20,000
protein-coding genes, each containing the information
needed to determine physical
and biological traits of humans.
An allele is a form of that gene. A
gene may have two or more
versions.
Each offspring inherits
1 allele from each of their
parents. If alleles are the same,
the offspring is homozygous. If
alleles are different, the offspring
is heterozygous.
46
What is allele frequency?
The allele frequency is
determined by quantifying the
prevalence of copies of an allele
of that gene in the population.
These frequencies reflect the
diversity of that genetic locus in
the population.
Changes in allele frequencies can
be meaningful and suggestive of
positive or negative selection for
that allele
47
What is fixation?
When one allele goes to 100%, it is
called fixed
48
Describe the changes in the duffy allele across time
Duffy antigen gene - DARC FY*B (“wild-type”)
* Duffy antigen gene - DARC FY*A (non-synonymous SNP in gene)
--> results in functional duffy receptor
* Duffy antigen gene - DARC FY*O (non-synonymous SNP in promoter)
--> results in Duffy-negativity
49
What is a polymorphic gene?
When variation exists (multiple
alleles in the population
50
What is positive genetic selection?
When a trait (the phenotype associated with a particular
genetic allele) has higher fitness, the associated allele will increase in that
population over time
51
What is negative genetic selection?
When a trait has lower fitness in the population, the associated allele will decrease in that population over time
52
What is adaptation?
A trait (the phenotype itself) that has evolved genetically by natural
selection, that confers a fitness advantage or disadvantage in a given environment.
Typically, it can be pinned down to something even more specific than that (a specific external selective pressure, e.g. pathogen or diet)
53
Give an example of positive selection and adaptation
DARC (duffy blood group antigen) gene deletion appears to be under positive selection. The adaptation of having red blood cells with no receptor that Plasmodium vivax can bind to appears to have given a fitness advantage.
54
What are the two theories suggested to explain the origins of homo sapiens?
- Multi-regional Model
- Out of Africa Model ß most accepted model
* Genomic evidence supports this
theory
* Homo sapiens migrating out of
Africa is the most widely
accepted explanation
55
What is the evidence for the out of Africa model?
1. There is more human genetic diversity in Africa compared with the rest of the world put together
2. The origin of mitochondrial DNA has been traced back to a human in Africa who lived between 50,000 to 500,000 years ago. Mitochondrial DNA can be traced exclusively to
the maternal side because it is in the cell cytoplasm, and the female contributes the cytoplasm through the egg (one’s mtDNA is almost identical as their mothers).
3. Similar research studying the Y chromosomal DNA (which is passed from male to male) also traces back to an individual male in Africa
4. Other areas of evidence relate to anthropological and geological findings
56
When did the out of Africa model happen
Some studies date this around
125Kya
57
What are the two members of homo genius
1. Homo neanderthalis (Neanderthals)
* Lived on Earth between 250,000
and 28,000 years ago
* Distributed between what is now
Europe and Central Asia
* Thought to have gone extinct
due to competition from Homo
sapiens
2. Homo sapiens (modern humans)
* Expanded out of Africa
approximately 125,000 years
ago
* Period of co-existence with
Neanderthals in Europe/ Asia
between 125K – 28K yrs ago
58
What is admixture?
the result of when individuals from 2 or more previously isolated
populations interbreed
Ancestral population 1 breeds with Ancestral population 2, leading to a newly formed Admixed population
59
Explain the admixture between homo sapiens and homo neanderthalis
In 2010, genomics was performed on Neanderthal and Denisovan DNA, collected from
fossils (bones) determined to be from these groups
* Comparison of Neanderthal & modern human genomes reveals interbreeding within the group of modern humans that migrated out of Africa (most overlap with human
genomes from Europe and Asia – in those groups, 1 – 2 % of genome)
60
Give examples of Neanderthal & Denisovan genes
1. 9 Neanderthal genes were associated with susceptibility to type two diabetes
2. Genes associated with increased hemoglobin concentration in the blood in Tibetan populations living at high altitude appear to come from
Denisovans
61
What is a population bottleneck?
an event that results in a large reduction in the size of the population. Events that can cause such bottlenecks include
environmental disasters, hunting, habitat destruction, and migrations.
62
Define the founder effect
This can be thought of as a very extreme case of genetic drift. In this
situation, a small number of individuals have gone through a “bottleneck” and a larger population has now descended from that smaller group of individuals. The frequency of alleles in the population will typically chance in this situation.
An example is polydactyly in the Amish population in Pennsylvania, which is thought to have arisen
from just 200 individuals.
63
What is the impact of a population bottleneck?
There is a resulting decrease in the gene pool of that new population. Many of the alleles from the ancestral population are lost in the bottleneck
- The population post-bottleneck has lower genetic diversity than the
ancestral population
64
Define gene flow
This is the migration of specific parts of genetic material from one population to another. This is mentioned in last week’s article as one of the arguments against biological races in humans (strong evidence of gene flow across populations from different locations).
Contributors to gene flow include: migration and movement
between populations of that species in different locations, and subsequent mating and production of offspring.
65
Define pleiotropy
When a single gene has multiple functions.
We often think of one gene, one function, but biological is more complicated than that. What this means is that if there is a mutation in a gene with multiple functions, there will be multiple outcomes of that mutation.
In the case of non-neutral outcomes, all outcomes can be positive, all can be negative, or it can be mixed (antagonistic pleiotropy).
An example is phenylketonuria
(PKU) disease. A mutation in the gene encoding the phenylalanine
hydroxylase enzyme (which converts phenylalanine into tyrosine) results in
multiple outcomes in the body (eczema, pigmentation defects, and
intellectual disabilities).
66
Define penetrance
A measurement of the proportion of
individuals with a specific genetic variant who also show the phenotype of that variant.
67
Do Mendelian genetic diseases have high penetrances?
Yes.
If you were to draw a Punnett Square, you can predict who will have the disease
* Examples include: cystic fibrosis, sickle cell disease, Duchenne muscular dystrophy
68
Do complex genetic diseases have high penetrance?
No.
If you were to draw a Punnett Square, you cannot predict who will have the disease
* One or more genes may be jointly impacting disease outcome
* Physical and social environment also play a role and impact disease development
* Examples include: heart disease, diabetes, cancer
69
What is an evolutionary trade off?
A situation in which 2 traits are incompatible with one another, and one gets selected because it enhances fitness in that environment,
while the other trait is lost or diminished (but is not as important in that environment for fitness)
* Trade-offs are environment-specific.
70
What is fitness?
The ability of an organism to pass on its genetic material to its offspring
(reproductive success), which is impacted by how well an organism is adapted to surviving and reproducing in a given environment
71
What is a diametric disease?
The result of evolutionary trade-offs, in a medical sense.
They are sets of traits, conditions or diseases that show opposite patterns in their prevalence (an increased risk of one necessitates a decreased risk of another)
72
What is a balancing selection?
A selection process by which multiple different alleles of one gene are maintained in the gene pool
because this enables maximum fitness of the population. No one of the alleles will ever be pushed to fixation in this environment.
73
Give examples of diametric trade offs
1. Trait trade-off: Birth weight in newborn human babies.
- Higher birth weight facilitates a
higher chance of survival in the
first few weeks of life, but too
large of birth weight has
increased mortality. Evolution
thus favors a trade-off between
these extremes.
2. Disease trade-off: Sickle cell status in humans in malaria-endemic regions prior to the development of drugs or vaccines for malaria.
- Having 1 copy of the sickle cell
gene confers higher survival
when infected with malaria, but
having 2 copies of the gene
increases mortality by causing
sickle cell disease.
74
Give an example of positive and negative selection
Positive selection: Lactase persistence in humans, via a mutation in the promoter of the
lactase gene, allows humans to digest milk into adulthood
Negative selection: Genetic diseases that disrupt immune function, termed primary immunodeficiencies (with onset in early childhood).
75
What is the red queen hypothesis?
the coevolutionary theory
that organisms must constantly evolve and adapt in order to survive as a species when they are in an
ecosystem with an evolving
opposing organism
76
What are the strongest selective forces on humans and why
Infectious diseases caused by pathogens (e.g., bacteria, viral, parasitic organisms that infect
and cause disease in humans.
1. Pathogens can reduce the fitness of their host. They can reduce the reproductive potential of their human hosts by causing illness, and death
2. Humans are thus under evolutionary pressure to evolve to better survive in an environment
with pathogens.
3. Selection drives the evolution of traits that affect how humans content with pathogens
77
What makes a pathogen a pathogen?
1. All pathogens enter the host (through the skin, or some orifice of the body).
2. All pathogens cross one or more barrier(s) of the host immune defenses to establish their population within the habitat of the host (e.g., break through skin, mucosa, hide inside cells to evade the innate immune system, mask themselves with different surface proteins to evade adaptive immune
system)
3. All pathogens multiply within the host. They may multiply asexually (e.g., binary fission, schizogeny) and/or they may multiply sexually (e.g., male and female forms undergo fertilization to form zygotes).
4. Obligate pathogens exit and infect another host. For those pathogens
that are obligate pathogens, they must transmit themselves to another
host. Otherwise, they will not maintain their population.
78
Match the diease to its parasite
1. Malaria
2. Tuberculosis
3. Smallpox
4. Cholera
5. AIDS
1. protozoan Plasmodium genus
2. Mycobacterium tuberculosis
3. Variola virus of the orthopoxvirus family
4. Vibrio cholerae
5. Human immunodeficiency virus (HIV)
79
What type of pathogen is selection most evident for?
Pathogens that have been with humans for longer periods of time
(malaria, tuberculosis, smallpox, leprosy, and cholera).
* Selection is less evident for pathogens that have been with humans for a shorter periods of
time (HIV, Sars-CoV-2)
COVID-19
80
How is evidence of natural selection related to pathogens detected in humans?
Natural selection leaves behind a genetic signature. While the
adaptation itself (the trait) is a phenotypic change in the human host, the underlying genetic signature will show evidence of a mutation
having arisen at some point and genetic variation now existing at a
particular locus in the genome (in the case of a SNP)
`
* Next generation DNA sequencing is used to detect genetic variants
that may be related to selection. The way that it is analyzed can help
find what these variants are associated with:
* Genome Wide Association Study (GWAS)
* Scans for natural selection
81
What is the human genome project?
An international effort that started in 1991 and concluded in 2003
with the first complete human genome sequence that was made
available to scientists for study
* 3 billion bases were sequence, covering 99% of the human genome’s
gene-containing regions, and revealing that we have just over 20,000 genes
* The identification of over 3 million SNPs, indicating diversity in the
human genome
82
How is genetic & functional diversity studied?
Linkage analysis – a technique for tracing patterns of disease inheritance in families that appear to have a high-risk for a particular disease
* Uses inheritance information and searches for piece of chromosome that is present in each
individual with that disease
* A “marker” is identified (some region of the chromosome) and that marker must be present in all
members with the disease, and absent in all members without the disease
* Principal method for determining risk of genetic disease prior to the genetic sequencing era
We now more commonly use known polymorphisms to determine risk (mutational analysis)
* Restriction enzymes could be used to cut DNA and will produce a different pattern on
a gel if a different sequence exists at that locus – (Restriction Fragment Length Polymorphisms, RFLPs)
* DNA sequencing can be used to directly read across a particular locus of the genome and determine what base pairs are in each position (Single Nucleotide Polymorphisms, SNPs)
83
Describe the process of DNA sequencing
Sequencing means to determine the precise order of bases in a piece of DNA
* An enzyme called DNA polymerase naturally occurs in cells and creates new pieces of DNA during replication
* To determine the sequence of an unknown piece of DNA, sequencing labs will add DNA polymerase + fluorescently labeled nucleotide bases to a tube
* Each time a particular base is added, a different color lights up. A machine then reads the order of the lights to determine the sequence
84
There are genetic variants in humans associated with
resistance to malaria.
What do these variants have in common?
Many of them relate to the red blood cell. Several relate to hemoglobin.
85
Describe the important stuff about hemoglobin
Hb is a tetrameric, iron-containing protein inside red blood cells (RBCs) which performs oxygen transport
across the body
Hb is comprised of 2 pairs of polypeptides (alpha, beta), which are encoded on chromosomes 16 and 11
Fetal hemoglobin (Hb F) has a pair of alpha and a pair of gamma chains. After birth, gammas are replaced
by betas
Sickle cell (Hb S) is caused by a glutamate to valine substitution on the Hb beta gene (a mutation in the
genome leads to a amino acid substitution), an altered Hb beta molecule, and subsequently a mutant
protein, and a sickle-shaped RBC
86
Who has an advantage if infected with malaria?
Individuals who are
heterozygous for the sickle cell
mutation have a survival
advantage if infected with
malaria
87
What does humans innate defense against malaria involve?
the spleen.
The spleen’s job is to remove old
and/or altered RBCs from circulation
* Blood circulates through the body at a rate faster than once per minute
* About 25% of the body’s blood volume is in the spleen at any given time
* Once marked as abnormal, splenic macrophages can phagocytose
and/or pit RBCs, thereby eliminating parasites
88
How does the sickle cell trait confer
resistance to malaria?
Once HbAS RBCs are subject to low oxygen they can begin to sickle (hemoglobin polymerizes into elongated chains)
* The sickled cell itself is more likely to be taken up by macrophages (due to its sickled state)
* The parasites within the sickled cell have been shown to not grow and develop as fast as they do in non-sickled cells
* Sickled RBCs do not present the PfEMP1 antigen as well as non-sickled RBCs and do not bind as well to the endothelium, due to the oblong shape of the cell. This reduces cytoadherence, increasing the
number of parasitized RBCs that flow
through the bloodstream and are
eliminated by the spleen
89
What is Trypanosomiasis disease?
Sleeping sickness
Two stages
* 1st stage: Peripheral blood
* 2nd stage: Central nervous system (after crossing blood-brain barrier)
Gambian form (West African sleeping sickness)
* Slow disease progression / chronic
* 1st stage: 1 to 2 years of mild symptoms (intermittent fevers, headache, malaise)
* 2nd stage: 1 or more years of neurological symptoms (confusion, sleepiness)
* If left untreated, leads to death within a few years
Rhodesian form (East African sleeping sickness)
* Rapid disease progression / acute
* 1st stage: 1 to 2 weeks of symptoms (fevers, headache, joint ache, rash)
* 2nd stage: months of neurological symptoms (mental deterioration leading to coma)
* If left untreated, leads to death within a few months
90
What is population structure?
The existence of varying amounts of genetic relatedness among certain subgroups within the sample
* Commonly used in the analysis of genomic variation across populations
91
What are the two main ways that population structure is analyzed?
Principal Components Analysis
Admixture proportion inference
92
What is principal component analysis?
A method for reducing a multi-
dimensional dataset into a smaller number of dimensions that can then
be investigated with a visual analysis of clustering, and analyzing using
more straight-forward statistical comparisons
93
What is Admixture proportion inference
Admixture proportion inference is a mathematical modeling method to
estimate the proportion of each individual’s whole genome that is derived from several source populations
