Transcript Lecture 11-POSTED-BISC441-2012

The evolutionary biology of morning sickness: disease,
defense, or outcome of maternal-fetal conflict?
Diseases, defenses, and byproducts: “Morning sickness”
(1) What is ‘morning sickness’?
(2) Hypotheses for the causes of morning sickness
EVALUATION OF THREE ALTERNATIVES
(a) Protection of fetus and mother from food-borne
infections and toxins
(b) Maternal/fetal conflict & screening of embryo quality
(c) Stimulation of placental growth via alterations to
maternal physiology
(1) What is ‘morning sickness’?
(a) Not just morning, and not a ‘sickness’ per se; also called
“nausea and vomiting of pregnancy” (NVP), or ‘emesis gravidarum’
(b) Affects over 80% of women worldwide, severity is a continuum
(c) Affects healthy pregnant females, who have healthy babies
(d) Most common in first trimester
(e) Causes reduced food intake, more-selective choice of food; also
may involve food cravings
(f) Proximate cause is unknown, quelled by thalidomide
(g) In severe cases (about 1%) of females, called hyperemesis
gravidarum, involves fluid and weight loss, severe enough for
hospital admission, can be life-threatening
Nausea and vomiting in pregnancy also has negative
impacts on woman, family relationships, and
working abilities;
-Anxiety and worry about effects on fetus
-Cited as reason for elective abortions, smaller family size
-47% of working women with NVP feel job efficiency is reduced,
-35% lose work time (mean loss of 62 working hours per woman),
and
-25% lose time from housework (mean loss of 32 hours per woman).
WHY COMMON AND PERSISTENT, GIVEN NEGATIVE ASPECTS?
HYPOTHESIS (a):
Protection of fetus and mother from
food-borne infections and toxins
(Sherman and Flaxman 2002,
and earlier studies)
NVP is an adaptation of mothers and fetuses to expel
foods that contain dietary toxins (such as plant secondary
compounds) or infectious agents, and to avoid eating
such foods in the first place
Adaptive functions of such expulsion and avoidance:
(i) help prevent miscarriage and birth defects
(ii) also help protect the mother, given that the maternal
cell-mediated immune system is depressed in pregnancy
The mother and embryo protection hypothesis
High nausea and vomiting
Avoid bad foods
Reduced rate of miscarriage and
birth defects
Testing the mother and embryo protection hypothesis: six
predictions
Percent
with NVP
(1) NVP should peak when embryo is most susceptible to
dietary toxins and infection, and when mother’s
immune system is most depressed
0.6
0.4
0.2
0
Sensitive
Fetal organ
0
5
CNS
H
UL
Ey
LL
T
P
EG
E
10
15
20
25
30
35
40
Post-menstrual week of
pregnancy
0
5
10
15
20
25
30
35
40
Post-menstrual week of pregnancy
(2) Avoided foods
should contain plant
toxins or pathogenic
microbes, but craved
food should not
(3) Aversions to potentially harmful foods should peak in the
first trimester when organogenesis is most sensitive to
disruptions
(4) Presence and magnitude of NVP should be positively
associated with favorable outcomes of pregnancy
MISCARRIAGES
25
NVP
20
No NVP
15
10
5
0
1
2
3
4
5
6
7
Study
State no association with low birth weight, birth defects, prematurity
More data on why it is good to have NVP
(5) Expression of NVP should depend on diet and should occur
least often among women who are seldom exposed to
dangerous food -> test for local adaptation with comparative
method
Flaxman and Sherman 2002
(6) Alleviating NVP should leave embryo more vulnerable to
harmful substances
Meta-analysis of 24 studies by Seto et al. (1997):
Women who took anti-emetic drugs (antihistamines) were
slightly and significantly less likely to bear children with birth
defects
But consider:
(a) women might have developed aversions before
taking anti-emetics, or
(b) stronger symptoms may have caused anti-emetic use and
positive outcomes, or
(c) positive outcomes may have been due to antihistamine use
Some questions
about the mother and
fetus protection
hypothesis
High nausea and vomiting
Avoid bad foods
(1) Might there be a
Reduced rate of miscarriage and
common cause of NVP
birth defects
and better outcomes?
(2) What about the physiological
mechanism? Who controls it?
(3) Why not just develop
Pike (1997): women in
food aversions without NVP?
Kenya with NVP more than
(4) Are societies studied representative twice as likely to lose fetus, baby;
likely due to nutritional deficits
of human evolutionary history?
(5) Are aversions and cravings specifically adaptive
to pregnancy (eg, what about chemotherapy nausea)?
(6) Where is the evidence for infectious-disease,
teratogenic effects of putatively-harmful foods?
HYPOTHESIS (b):
Screening of
embryo quality
HYPOTHESIS b:
Screening of
embryo quality
High production of hCG by healthy embryo, fetus, due to
selection on fetus to maintain pregnancy in situation
of maternal-fetal conflict - ‘test’ of embryo metabolic
abilities, to produce large amounts of a protein
High NVP
Good outcome, low miscarriage rate
(BYPRODUCT****)
Basis, rationale for embryo quality hypothesis
(1) Maternal-fetal conflict is predicted by inclusive fitness theory
(2) A potential conflict is expected over maintenance of
pregnancy:
->fetus selected for phenotypes (and underlying alleles)
that maintain pregnancy,
->mother is selected to (a) abort any fetus in poor circumstances,
(b) screen fetuses for quality (lack of genetically-based defects)
Especially strong potential conflicts in humans, which have
enormous levels of parental investment; costs associated
with infanticide are much larger than early miscarriage costs
Parent-offspring
conflict is due to
higher relatedness
to self/own offspring
than to sib/nieces,
nephews
r = 1/2
r = 1/4
Mom maximizes her inclusive
fitness at a lower level of
maternal investment than the
level that maximizes inclusive
fitness for any one offspring
Selection for alleles in mom ‘for’
adaptations that constrain
investment
Selection for alleles in offspring
‘for’ adaptations to take more
from mom, to the point that
negative effects on other sibs
are not too great
Mom
Kid
MAIN STAGES OF
CONFLICT:
(1) Survival of conceptus
(2) Growth in the womb
(3) Survival at birth
(4) Investment in childhood
(5) Inheritance as adult
Strategies (variation)
available?
Manifestations of maternal-fetal conflict
Spontaneous abortion - Should mom maintain the pregnancy?
Depends on the quality of the fetus and state of the mother. These
hinge on cost/benefit issues in relation to possible future
pregnancies.
POSSIBILITIES
(1) Mother and baby BOTH want pregnancy maintained
(2) Baby wants pregnancy maintained, mother does not
CONFLICT
(3) NEITHER wants pregnancy maintained (embryo selected to
abort self)
What is a conceptus to do?
SHOUT that they are here and take over the system that maintains
pregnancy as rapidly as possible
hCG bypasses pathway and stimulates
the corpus luteum to produce progesterone
anterior pituitary
and by the 8th week of pregnancy,
luteinizing
hormone
produces enough P to sustain pregnancy
on its own.
chorionic
gonadotropin
placenta
progesterone
corpus luteum
progesterone
uterus
How might this ‘subversion system’ have evolved??
Scenario for evolution of subversion by hCG
(1) Mother alone maintains early pregnancy
via LH, regulated to maximize her inclusive fitness
(2) Embryo is selected to also produce LH, released into
mother’s bloodstream, to help maintain the pregnancy
(3) Mothers selected for reduced LH production, to abort
less-vigorous fetuses -> ‘arms race’ ensues
(4) Series of gene duplications involving gene for LH,
evolution of hCG gene via positive selection
(baby evolves subversion, mom evolves ability to abort
subnormal embryos)
The gene for one of the two hCG subunits
(CGbeta subunit, CGbeta) arose by duplication
from the luteinizing hormone beta subunit gene (LHbeta)
Positive selection on
chorionic gonadotropin
gene
Other evidence salient to the
embryo quality hypothesis
(1) There is a close association
between the timing of hCG
production and the timing
of nausea and vomiting
How hCG
from baby
apparently
makes mum
pregnancy sick
Proximate
mechanism
Other evidence salient to the embryo quality hypothesis
(2) Low hCG production is associated with early pregnancy loss
(3) High hCG production is often associated with hyperemesis
gravidarum
(4) Higher hCG production with female fetus, and higher
levels of nausea and vomiting with female fetus - WHY?
(5) Higher hCG production with twins, and higher
levels of nausea and vomiting with twins
(6) Evidence that most early miscarriages are due to
intrinsic genetic causes, mainly chromosomal defects
(aneuploidies), not diet (clinicians use hCG production as a
measure of embryo health!)
(7) Embryos with trisomy 21 produce exceptionally-high
levels of hCG, and mothers have high nausea, vomiting
Other evidence salient to the embryo quality hypothesis
Is hCG subject to genomic imprinting? (Haig 1993)
Humans: are two kinds of triploid fetus
Diandric - large fetus, large placenta, high hCG in mom
Digynic - small fetus small placenta, low hCG in mom
-> due to paternal expression of hCG?
hCG is also in genomic region with imprinted genes
Horses have independently evolved a CG and show
paternal expression of the gene
Evolution of genomic imprinting in placental mammals
under multiple paternity and high maternal investment:
Paternal
gene
Relatedness of paternal gene in offspring,
to siblings, goes from 0.5 to 0 as we go from
monogamy to polygamy
Maternal gene
Relatedness of maternal gene in offspring,
to siblings, is always 0.5
Paternally-expressed genes are expected to be more
‘selfish’, with regard to mother-offspring interactions
Evidence against the embryo quality hypothesis?
(1) Absence of nausea and vomiting in some pregnancies, and
apparently some societies
-> many factors other than embryo quality are involved
(2) Apparent absence of nausea and vomiting in other species
of mammals, which are subject to maternal-fetal conflicts?
-> only a few species (horses, humans) have evolved
the mechanism, chorionic gonadotropins
HYPOTHESIS b (reviewed):
Screening of
embryo quality
High production of hCG by healthy embryo, fetus, due to
selection on fetus to maintain pregnancy in situation
of maternal-fetal conflict
High NVP
Good outcome, low miscarriage rate
(BYPRODUCT,
usually only a nuisance to females)
HYPOTHESIS (c):
Stimulation of
placental growth
Pregnancy sickness and stimulation of placental growth:
rational and evidence
Nausea and vomiting
Reduced food intake in first trimester
Placental development stimulated
(1) Dutch hunger winter - First trimester undernutrition
associated with higher placental weights
(2) Epidemiologic studies - increased food intake in first
trimester results in infants with smaller placental and birth
weights (nutrient partitioning is favoring the mom)
(3) Animal husbandry - well nourished sheep,
mate them, move them to poor pasture ->
best outcomes of pregnancies
Pregnancy sickness and stimulation of placental growth:
mechanism?
-> Reduced nutrient intake in early pregnancy lowers
maternal levels of anabolic hormones, insulin, and IGF-1.
-> This helps to ensure ‘sufficient’ nutrient delivery to placenta
-> Fetal growth is regulated by IGF-2 during this period!
(IGF-2 is imprinted and paternally-expressed, as you recall).
It is regulated by IGF-1 in 2nd, 3rd trimesters.
-> Placenta also secretes leptin into mother’s blood in
first trimester, which suppresses appetite
Pregnancy sickness and stimulation of placental growth:
how and where is selection working here?
Benefit to both? But fetus is altering the mother’s physiology
Benefit to fetus?: fetus makes mother ill to gain increased
share of maternal resources
CAN THE THREE HYPOTHESES FOR MORNING
SICKNESS BE RECONCILED?
(a) Toxin/pathogen: NVP is adaptive to mom
and fetus, as a mechanism to avoid bad foods
(b) Embryo quality/maternal-fetal conflict:
NVP is a non-adaptive byproduct of maternal-fetal conflict
(c) Placental growth: NVP is adaptive for mom and fetus,
as a mechanism to reduce food intake in first trimester
Functional design
Comparative method
Measurement of selection
NEED DIFFERENTIATING PREDICTIONS of the
three hypotheses
NEED TO KNOW THE MECHANISMS in more detail
(functional design of physiology, genetics)
Imprinting?
Proximate, Ultimate causes
NEED TO KNOW WHO BENEFITS in what
situations, in traditional societies
EVALUATING, RECONCILING THE HYPOTHESES
Fetus, placenta secrete hCG -> helps maintain
pregnancy and reduces maternal food intake
(via nausea), which stimulates placental growth??
Might protection from toxins, pathogens be a
byproduct of this system??
Might variation in aversion to different foods be
a non-adaptive byproduct of general nausea??