Transcript 440evolmed

Evolutionary Medicine
I.
Humans as Recently Evolved, Genetically Diverse Animals
A. Adaptations to Local Environments
1. LCT – locus coding for lactase production
- mammals shut down lactase production after weaning
- strong selective sweep in Europeans and Africans that drink milk as adults
- European sequences: ~ 9000 years old but show spread about ~4000 ya
- African sequences ~ 5000 ya, consistent with spread of cattle
- convergent evolution of different variants with same effects
I.
Humans as Recently Evolved, Genetically Diverse Animals
A. Adaptations to Local Environments
2. Malaria Resistance
- Sickle cell
(resistance to
Plasmodium falciparum malaria)
I.
Humans as Recently Evolved, Genetically Diverse Animals
A. Adaptations to Local Environments
2. Malaria Resistance
- FY*O allele – Resistance to
Plasmodium vivax malaria
I.
Humans as Recently Evolved, Genetically Diverse Animals
A. Adaptations to Local Environments
3. High Latitude
- Light Pigmentation
Greenlandic Inuit show genetic signatures of diet and climate adaptation
Matteo Fumagalli, et al. Science 2015.
Significant differences in genes for
omega-3 fat metabolism (FADS) in
Greenland Inuit (GI) compared to
Europeans (CEU) and Chinese
(CHB). Much higher levels of serum
desaturases.
TBX15 stimulates adipocytes that
burn lipids for heat, and may be an
adaptation to cold.
Greenlandic Inuit show genetic signatures of diet and climate adaptation
Matteo Fumagalli, et al. Science 2015.
Significant differences in genes for
omega-3 fat metabolism (FADS) in
Greenland Inuit (GI) compared to
Europeans (CEU) and Chinese
(CHB). Much higher levels of serum
desaturases.
TBX15 stimulates adipocytes that
burn lipids for heat, and may be an
adaptation to cold.
Two other loci associated with
decreased height and weight
Selection on single genes and polygenic traits in Britons over the last 2000-3000 years
Yair Field et al. Science 2016;354:760-764
Published by AAAS
I.
Humans as Recently Evolved, Genetically Diverse Animals
A. Adaptations to Local Environments
- Failure to Adapt and ‘Plesiomorphic Traits’
The ‘Hygiene Hypothesis’ of allergies and
autoimmune disorders
Exposure to weak pathogens is required to
stimulate and ‘educate’ the immune system
Mice reared in bacteria-free environment develop
auto-immune disorders
Hylobacter pylori, a stomach bacterium of humans, was ubiquitous in our
species before antibiotics. Only 20% of American children have it now.
Those who have it are 59% less likely to have asthma, and have lower
rates of hay fever and eczema. H. pylori triggers the development of Th17
cells, that regulate responses to bacteria. BUT: increases chance of
stomach cancer.
Initial exposure
acclimatization
I.
Humans as Recently Evolved, Genetically Diverse Animals
A. Adaptations to Local Environments
- Failure to Adapt and ‘Plesiomorphic Traits’
Type-2 Diabetes and the ‘Western Diet’
“Thrifty Genotype Hypothesis”: Populations with historically
low sugar and fat in the diet have genes to store calories as fat
during times of plenty (low insulin production and uptake), to
burn during lean times.
Now there are no lean times and fat is just stored.
I.
Humans as Recently Evolved, Genetically Diverse Animals
A. Adaptations to Local Environments
B. Pair-bonding and Oxytocin
A and B: Childhood stress is negatively associated with oxytocin
levels when the grow into adults.
Couples who are affectionate (gentle
touching) have higher oxytocin levels
than couple that don’t.
I.
Humans as Recently Evolved, Genetically Diverse Animals
A. Adaptations to Local Environments
B. Pair-bonding and Vasopressin
- Prairie voles pair bond, and have high levels of
expression for a vasopressin receptor (AVPR1a) in forebrain.
- Male meadow voles are polygamous, and have low
levels of expression of AVPR1a in forebrain.
- Inducing expression of meadow vole receptor in
males causes pair-bonding… a change in mating system.
I.
Humans as Recently Evolved, Genetically Diverse Animals
A. Adaptations to Local Environments
B. Pair-bonding and Vasopressin
- Humans (Wahlum et al. 2008).
- Humans have AVPR1a on Chromosome 12.
- there is a polymorphic flanking region with three repeat sequences that are polymorphic:
(GT)25 dinucleotide repeat ( = GT)
(CT)4-TT-(CT)8-(GT)24 repeat ( = RS3)
(GATA)14 ( = RS1)
- (variants may be associated with autism, age of first intercourse, and altruism)
Wahlum et al. (2008) used Swedish twin database (552 same-sex twins)
- genotypes twins and scored their relationships on a “Pair-Bonding Scale” used for other primates
I.
Humans as Recently Evolved, Genetically Diverse Animals
A. Adaptations to Local Environments
B. Pair-bonding and Vasopressin
- Humans (Wahlum et al. 2008).
Men
Repeat
Women
df
F
P
GT25
21, 148
0.39
0.99
RS1
16, 187
1.03
RS3
19, 157
2.48
Effect just for males, as in voles…
Repeat
df
F
P
GT25
18, 138
1.05
0.41
0.43
RS1
15, 197
0.99
0.46
0.001
RS3
21, 166
1.19
0.27
Association between different RS3 alleles and the Partner Bonding Scale in men
Allele
Freq
Percent
Mean
df
F
P
320
21
2.3
48.8 (6.21)
1, 12
1.52
0.24
330
92
9.9
47.6 (7.18)
1, 37
0.21
0.65
332
128
13.8
47.5 (6.45)
1, 50
0.06
0.81
334
371
40.0
46.2 (6.23)
1, 130
16.35
<0.0001
336
359
38.7
47.6 (6.35)
1, 133
1.51
0.22
338
170
18.3
48.3 (6.21)
1, 77
4.73
0.03
340
263
28.4
47.5 (6.56)
1, 106
0.40
0.53
342
30
3.2
47.0 (4.49)
1, 12
0.05
0.82
344
23
2.5
45.6 (6.43)
1, 8
1.64
0.24
346
126
13.6
46.7 (6.87)
1, 60
1.30
0.26
348
37
4.0
47.9 (8.47)
1, 16
0.36
0.55
Effect of 0, 1 or 2 334 alleles on male reports on the Partner Bonding Scale, marital crisis, and marital status
Number of 334 alleles
Measure
0
1
2
df
F
P
8.40
0.0004
Mean score for the Partner Bonding Scale in the three groups
LOWER
PBS
Partner Bonding
Scale
48.0 (6.50)
46.3 (6.16)
45.5 (6.71)
2, 143
Frequency and column-wise percentage of subjects reporting marital crisis/threat of divorce in the three groups
Have you experienced marital crisis or threat of
divorce during the last year?
More Marital
Crisis
No
469 (85%)
277 (84%)
27 (66%)
Yes
81 (15%)
51 (16%)
14 (34%)
2, 143
5.00
0.008
Frequency and column-wise percentage of subjects being married or cohabiting in the three groups
Marital status
Less
Marriage
Married
Cohabiting
457 (83%)
275 (84%)
28 (68%)
96 (17%)
52 (16%)
13 (32%)
2, 143
4.36
0.01
Association between 334 alleles in men and their wives' reports of marital qualities
(mean)
β
Unadjusted
18.0 (2.99)
17.4 (2.92)
Adjusted
—
Unadjusted
Quality
Affectional
expression
Dyadic
consensus
Dyadic
cohesion
Dyadic
satisfaction
One or two 334
No 334
(mean)
df
F
P
−0.64
1, 113
10.08
0.002
—
−0.39
1, 111
4.30
0.04
65.4 (8.11)
63.9 (8.57)
−1.46
1, 117
6.92
0.01
Adjusted
—
—
−0.82
1, 115
2.46
0.12
Unadjusted
19.5 (4.34)
18.9 (4.10)
−0.60
1, 116
4.27
0.04
Adjusted
—
—
−0.20
1, 114
0.53
0.47
Unadjusted
43.3 (3.14)
43.2 (2.92)
−0.12
1, 111
0.49
0.49
334 allele associated with increased hippocampal m-RNA, amygdala activity, and overexpression in autism
I.
Humans as Recently Evolved, Genetically Diverse Animals
A. Adaptations to Local Environments
B. Pair-bonding and Vasopressin
C. Kin Selection / Infanticide
I.
Humans as Recently Evolved, Genetically Diverse Animals
A. Adaptations to Local Environments
B. Pair-bonding and Vasopressin
C. Kin Selection / Infanticide
D. Physical Ailments
I.
Humans as Recently Evolved, Genetically Diverse Animals
A. Adaptations to Local Environments
B. Pair-bonding and Vasopressin
C. Kin Selection / Infanticide
D. Physical Ailments
I.
Humans as Recently Evolved, Genetically Diverse Animals
A. Adaptations to Local Environments
B. Pair-bonding and Vasopressin
C. Kin Selection / Infanticide
D. Physical Ailments
“hunch” back
‘sway’ back
scoliosis
I.
Humans as Recently Evolved, Genetically Diverse Animals
A. Adaptations to Local Environments
B. Pair-bonding and Vasopressin
C. Kin Selection / Infanticide
D. Physical Ailments
Pregnancy and lower back pain from
lordosis
I.
Humans as Recently Evolved, Genetically Diverse Animals
A. Adaptations to Local Environments
B. Pair-bonding and Vasopressin
C. Kin Selection / Infanticide
D. Physical Ailments
Men: Kyphotic at 1 and 2
lordotic at 4 and 5
Women: kyphotic at 1
lordotic at 3-5
male
female
I.
Humans as Recently Evolved, Genetically Diverse Animals
A. Adaptations to Local Environments
B. Pair-bonding and Vasopressin
C. Kin Selection / Infanticide
D. Physical Ailments
I.
Humans as Recently Evolved, Genetically Diverse Animals
A. Adaptations to Local Environments
B. Pair-bonding and Vasopressin
C. Kin Selection / Infanticide
D. Medical Ailments
Impacted 3rd molar
I.
Humans as Recently Evolved, Genetically Diverse Animals
A. Adaptations to Local Environments
B. Pair-bonding and Vasopressin
C. Kin Selection / Infanticide
D. Medical Ailments
Impacted 3rd molar
I. Humans as Recently Evolved, Genetically Diverse Animals
II. Evolving Host-Parasite Relationships
A. Rapid Within-Host Evolution
- mutation rates high
Variation and Rapid Response to
- reproduction is rapid
Selection by Immune system
HIV
Increased Energy
use + virulence
I. Humans as Recently Evolved, Genetically Diverse Animals
II. Evolving Host-Parasite Relationships
A. Rapid Within-Host Evolution
B. Balanced by Transmission Rate and “between host” evolution
- if transmission rate is high, virulence and “within-host”
evolution dominates
- if transmission rates are low, selection favors strains that do
not kill their host
I. Humans as Recently Evolved, Genetically Diverse Animals
II. Evolving Host-Parasite Relationships
A. Rapid Within-Host Evolution
B. Between-Host Evolution
C. Response to Antibiotics
I. Humans as Recently Evolved, Genetically Diverse Animals
II. Evolving Host-Parasite Relationships
A. Rapid Within-Host Evolution
B. Between-Host Evolution
C. Response to Antibiotics
I. Humans as Recently Evolved, Genetically Diverse Animals
II. Evolving Host-Parasite Relationships
A. Rapid Within-Host Evolution
B. Between-Host Evolution
C. Response to Antibiotics
D. The Evolution of ‘Old’ Diseases
Herpesvirus 5 only infects humans,
but it’s relatives infect other
primates and radiated with primate
evolution
I. Humans as Recently Evolved, Genetically Diverse Animals
II. Evolving Host-Parasite Relationships
A. Rapid Within-Host Evolution
B. Between-Host Evolution
C. Response to Antibiotics
D. The Evolution of ‘Old’ Diseases
Human infections
E. The Evolution of ‘New’ Diseases
2012 – Saudis began dying of “Middle Eastern
Respiratory Syndrome” (30% fatality rate)
Smallpox - Variola major
Probably originated ~ 10,000 bc
Oldest possible case: Ramses V (~1150 bce)
Likely in India bce; China in 3rd century ce
Needs large population of susceptible hosts (children)
Probably a ‘new’ virus, needing pop of 200-300,000.
Many epidemics in Africa, Asia, and Europe
In late 1700’s – killed 400,000/year in Europe
Average mortality rate in Europe of 30-35%
In Western Hemisphere/Australia, mortality of 90%
‘Variolation’ was used to inoculate – 2% mortality rate
1796 - Edward Jenner used cowpox pus to vaccinate James
Phipps (8 yr old son of his gardener). Word spread and
vaccinations (with Vaccinia) became common in Europe.
Killed 300-500 million people in 20th century
1950’s – global eradication program began
1979 – WHO declares smallpox eradicated
Ramses V
“The origin of the Variola virus”. 2015. Viruses 7: 1110-1112
Camels introduced into East
Africa about 2500 bc, and a
period of dramatic climate
change may have stimulated
the jump of CPXV to new
hosts (camels, rodent,
human).
Human smallpox (specific)
(2000 bc)
Ramses V (1150 bc)
Naked soil gerbil (specific)
Camelpox (specific)
Monkeypox
Cowpox
Rodent
Reservoir
Also infect
humans
I. Humans as Recently Evolved, Genetically Diverse Animals
II. Evolving Host-Parasite Relationships
A. Rapid Within-Host Evolution
B. Between-Host Evolution
C. Response to Antibiotics
D. The Evolution of ‘Old’ Diseases
E. The Evolution of ‘New’ Diseases
The Ecological Context
Lyme Disease:
- fragmentation reduces patch size
- abundance of predators like fox
declined
- white-footed mice (host of Borrela
burgdorferi bacterium) increase.
- increase host density, increase
infection rate of ticks.
West Nile Virus
Low Diversity:
High Relative Abundance of Hosts
High Diversity:
Low Relative Abundance of Hosts
Swaddle and Carlos, 2008. PLoS one 3:e2488
I. Humans as Recently Evolved, Genetically Diverse Animals
II. Evolving Host-Parasite Relationships
A. Rapid Within-Host Evolution
B. Between-Host Evolution
C. Response to Antibiotics
D. The Evolution of ‘Old’ Diseases
E. The Evolution of ‘New’ Diseases
F. Attenuated Viruses
Infect non-human primates and continually
transfer them between new individuals,
adapting the virus to the new host.
When presented to humans, it still elicits an
immune response but does not infect human
cells and cause disease.
I. Humans as Recently Evolved, Genetically Diverse Animals
II. Evolving Host-Parasite Relationships
III. Antagonistic Pleiotropy
A. Cancer
- The benefits of cell division and healing when young increase mutation rates that cause cancer later.
- Children, with rapidly dividing cells, are more susceptible to environmental mutagens
I. Humans as Recently Evolved, Genetically Diverse Animals
II. Evolving Host-Parasite Relationships
III. Antagonistic Pleiotropy
A. Cancer
B. Other Diseases
III. Antagonistic Pleiotropy
A. Cancer
B. Other Diseases
Examples of antagonistic pleiotropy for genes that increase risk or severity of chronic inflammatory diseases
Genes
HLA DR4 (DRB1*04)
HLA B27
PTPN22 1858 C>T*
Evolutionary medicine and chronic
inflammatory state—known and new concepts
in pathophysiology. J. Mol. Med. 2012.
Chronic inflammatory
disease
Pleiotropic meaning outside of
chronic inflammatory diseases
(with selection advantage)
Refs.
Decrease of risk of dengue
Rheumatoid arthritis and
hemorrhagic fever (defense
[21]
other autoimmune diseases
against infectious agents)
Ankylosing spondylitis and
Decrease of viral infection
other axial forms of
[57, 58]
(defense against infectious agents)
spondyloarthritis
Higher body mass index, higher
Many autoimmune diseases waist-to-hip ratio in women
[59]
(storage of energy-rich fuels)
CTLA4 49 A>G
Better defense against hepatitis B
Many autoimmune diseases virus and Helicobacter pylori
[60, 61]
(defense against infectious agents)
NOD2/CARD15
Crohn’s disease
Hypertension (activation of the
sympathetic nervous system)
[62]