Transcript Lecture 3-POSTED-BISC441-2012

Genomic Conflicts, Health and Disease
(1) What are genomic conflicts and
how are they involved in health and
disease?
(2) Main forms of genomic conflict
(a) Parent-offspring conflict
(b) Genomic-imprinting conflict
(c) Sexual conflict
The logic & dynamics
of genomic
evolutionary conflict,
in relation to health
and disease
Frank & Crespi
2011, PNAS
(a) Parent-offspring
conflict is due to
higher relatedness
to self/own offspring
than to sib/nieces,
nephews
r = 1/2
r = 1/4
Autosomes:
Parent-offspring conflict
Parents value offspring equally.
Each offspring values itself 2 times more than it
values its sibling.
Parents will prefer an equitable distribution of
parental investment.
Offspring will prefer an inequitable distribution
of parental investment, with more to self
Conflict begins in the womb.
X chromosome alleles? Y chromosome alleles?
Mom maximizes her inclusive
fitness at a lower level of
maternal investment than the
level that maximizes inclusive
fitness for any one offspring
Mom
Kid
Selection for alleles in mom ‘for’ MAIN STAGES OF CONFLICT:
adaptations that constrain
(1) Survival of conceptus
investment
(2) Growth in the womb
(3) Survival at birth
Selection of alleles in offspring (4) Investment in childhood
‘for’ adaptations to take more
(5) Inheritance as adult
from mom, to the point that
negative effects on other sibs
Strategies (variation) available?
are not too great
Mother-offspring conflict example
Mother has 100 units
to invest in kids
Three kids to invest in:
Options
A
33 33 33
B
50 50 0
C
100 0 0
KIDS 1 2 3
Mothers fitness
A 3(.5) = 1.5*
B 2(.7) = 1.4
C 1(.9) = 0.9
Units->Survival
33->.5
50->.7
100->.9
Offspring 1’ s fitness
0.5 + 2(.5)(.5)=1.0
0.7 + 1(.5)(.7)=1.05*
0.9 + 0(.5)(0.9)=0.9
Conflict can exist over
(1) whether or not to ‘miscarry’
(2) invasiveness of the placenta
(3) the nutrient quality of maternal
blood -> blood glucose
(4) the volume of blood reaching the
placenta -> blood pressure
Maternal provisioning of a fetus is
associated with an ‘opportunity cost’
The opportunity cost translates into lower
expected fitness through other offspring
If extra resources are transferred to a given
embryo (you)
-> the embryo’s (your ) expected fitness
increases
-> the mother’s expected fitness via other
offspring decreases
TRADEOFF between
current & future reproduction
Conceptus
@ 9 days old
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.
AND WHO is in CONTROL of what?
POSSIBILITIES
(1) Mother and baby Both ‘want’ pregnancy maintained
(2) Baby ‘wants’ pregnancy maintained, mother does not
CONFLICT
(3) Neither ‘wants’ pregnancy maintained - WHY? WHEN?
What is a conceptus to do?
Shout that they are here and ‘take over’ the system that maintains
pregnancy as rapidly as possible
Pregnancy is maintained via the production
of LH and LH’s stimulation of progesterone
anterior pituitary
(P) production.
luteinizing
hormone
Temporary endocrine
corpus luteum
structure, from
ovarian follicle
progesterone
uterus
hCG bypasses this pathway and stimulates
the corpus luteum to produce progesterone
and by the 8th week of pregnancy,
anterior pituitary
produces enough P to sustain pregnancy
luteinizing
hormone
on its own.
human chorionic
gonadotropin
placenta
corpus luteum
progesterone
uterus
hCG bypasses this pathway and stimulates
the corpus luteum to produce progesterone
anterior pituitary
and by the 8th week of pregnancy,
luteinizing
hormone
produces enough progesterone to sustain pregnancy
on its own.
chorionic
gonadotropin
placenta
progesterone
corpus luteum
progesterone
uterus
Conflicts over food for the growing fetus:
(1) Invasion of the placenta into the uterine wall. Allows fetus to prevent cutoff of blood flow (modify spiral arteries), access matermal blood efficiently.
Disruption of the conflict system: pre-eclampsia
(2) Fast food for baby - amount of food depends on glucose levels in maternal
blood - you want more than mom wants to give you. Insulin keeps blood
sugar from getting dangerously high. hPL (placental lactogen) blocks
(bonds) maternal insulin.
Disruption of the conflict system: gestational diabetes
(3) More blood please! Amount of food also depends on maternal blood
pressure - you want mom’s blood pressure to be higher
Disruption of the conflict system: pre-eclampsia
“The border zone … is not a sharp line, for it
is in truth the fighting line where the conflict
between the maternal cells and the invading
trophoderm takes place, and it is strewn with
such of the dead on both sides as have not
already been carried off the field or otherwise
disposed of.”
Johnstone (May 1914)
Journal of Obstetrics and Gynaecology of the British Empire 25: 231
MAIN STAGES OF
PARENT-OFFSPRING
CONFLICT:
(1) Survival of conceptus
(2) Growth in the womb
(3) Survival at birth - infanticide
and baby fatness, cuteness
(4) Investment in childhood lactational amenorrhea, weaning,
tantrums, language, learning
(5) Inheritance as adult
How parent-offspring conflicts contribute to disease
(1) Disruption of ‘tugs-of-war’ over resources
(mild gestational diabetes or preclampsia leads
to a bigger, fatter baby but severe cases endanger the life
of both mother and fetus)
(2) Wastes of resources (release of compounds by placenta
that are ‘ignored’ by mother - hormonal ‘shouting’)
(3) Maladaptations in party that ‘loses’ in a conflict (mother ‘stuck’ with pregnancy, fetus takes fatty acids
direct from mom’s brain, fetus controls parturition time)
(4) Within-family ongoing verbal, physical
conflicts and psychological health and
well-being
Genomic Conflicts, Health and Disease
(1) What are genomic conflicts and how are they
involved in disease?
(2) Main forms of genomic conflict
(a) Parent-offspring conflict
(b) Genomic-imprinting conflict
from dad
What is genomic imprinting and why has it evolved?
Expression of a gene depending on whether
inherited from father or mother
Main arenas of imprinting effects on human health:
-Placenta
-Brain
-Carcinogenesis
-Stem cells
-In vitro fertilization
from mom
Imprinted
gene
expression
compared
to biallelic
gene
expression
How
imprinting
works, across
the life cycle
Why imprinting has evolved, in
placental mammals:
Asymmetries in parental
investment are high
• the mother alone gestates
and lactates
• all her children have 50% of
her genes
• the father contributes only a
single sperm
• mixed paternity is common
across births or broods
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
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
EXTREME CASE:
Mum’s
Brood
Maternal gene
Relatedness of maternal gene in offspring,
to siblings, is always 0.5
IMPRINTED GENES
(1) Silenced (‘imprinted’) when inherited from either the
father or the mother (-> parent of origin effects)
(2) Paternally-expressed (maternally-silenced) genes are
expected to be associated with increased demands
on the mother, by offspring
(3) Maternally-expressed genes are expected to be
associated with reduced demands on the mother
‘TUGS-OF-WAR’ can result
(eg IGF-II/IGF-IIR in pregnancy)
EXAMPLE: TUG-OF-WAR over fetal growth in pregnancy
In fetus:
IGF-II paternally expressed,
IGF-IIR maternally expressed
Paternally-expressed gene generates IGF-II,
Maternally-expressed gene IGF-IIR serves as
non-functional ‘sink’ that degrades IGF-II
WITHIN
A Fetal
Mouse:
Imprinted genes are ‘master regulators’ of placentation:
they control growth and differentiation
CONFLICT THEORY OF IMPRINTING
-> abundant support from empirical studies of
imprinted genes and growth, in mice and humans
(1) IGF2-IGF2R (Haig & Graham 1991 Cell)
(2) CDKN1C (Andrews et al. 2007 BMC Dev Biol)
(3) GRB10 (Charalambous et al. 2003 PNAS)
BeckwithWiedemann
Syndrome
2 doses IGF2
Mighty mouse
Normal sized
human
1 dose IGF2
SilverRussell
syndrome
0 doses IGF2
Effects of alterations to imprinted genes on the placenta in mice
KNOCKOUTS
*
Dysregulation of imprinted genes in the placenta is
an important cause of intra-uterine growth restriction
(IUGR) in humans
Imprinting
Placentation
Imprinting can cause
genetic disorders, if
both chromosomes
are inherited from
same parent
IMPRINTED GENE EXPRESSION IN THE PLACENTA
AND IN THE BRAIN
About 100 imprinted genes are known, many
more are predicted or apparent (need
validation)
Primary site of imprinted-gene expression is the
(‘social’) placenta, which mediates the transfer
of resources between mother and child
Small deviations in placental function can
benefit the child, or the mother
Large deviations are costly to both
The second-most important site of imprinted
gene expression is the (‘social’) brain
Imprinting & the brain
‘most imprinted genes will affect how much an offspring
receives from its mother, at the expense of sibs. Thus imprinting
is expected at loci that influence placental growth, suckling,
neonatal behavior, appetite, nutrient metabolism and postnatal
growth rate… it is worth considering the possibility that
imprinting influences appetite control and hypothalamic
function.’
After the placenta, genes are
most-commonly
imprinted in the brain
Chimeric mouse brain
The mother and the ‘maternal brain’
• is the prime
nurturer
• has equal number
of genes in all her
children (50%)
• her genes ‘build’
the part of the
brain that can be
nurtured and
exercise restraint:
the neo-cortex
The father and the
‘paternal brain’
• relies on his genes to
control growth,
development, and
behaviour
• other children in the
family need not share
his genes
• his genes ‘build’
the limbic brain
Paternally-expressed imprinted genes are especially commonly
expressed in the hypothalamus, where they affect
energy metabolism and other fundamental body functions
(food, activity level, sex, sleep)
Oppositely-imprinted disorders of the brain:
Prader-Willi & Angelman syndromes
• Angelman:
paternal additions
and/or maternal
deletions on
chromosome 15q1113
• Prader-Willi:
maternal
additions and/or
paternal deletions
on chromosome
15q11-13
Angelman Prader-Willi
•
•
•
•
•
prolonged suckling
frequent crying
hyper-active/sleepless
low pleasure threshold
severe retardation: no
language
• autism
Every mother’s worst fear, as
regards behaviour of a child
•
•
•
•
•
poor suckling
weak crying
inactive/sleepy
high pain threshold
affective psychosis
in adults
Complacent, easy on mom
b) Genomic-imprinting conflict
What is genomic imprinting and why has it evolved?
Expression of a gene depending on whether
inherited from father or mother
Main arenas of imprinting effects on human health:
-Placenta
-Brain
-Carcinogenesis
-Stem cells
-In vitro fertilization
Imprinting and Cancer:
Paternally-expressed
imprinted genes enhance
growth/proliferation; some
are ‘oncogenes’
Maternally-expressed
Imprinted genes constrain
growth/proliferation; some
are ‘tumor suppressors’
PNAS, 2003
Main mechanisms whereby alterations to imprinted genes promote cancer development
BWS = BeckwithWiedemann syndrome
Alterations to genomic imprinting alter the properties of
embryonic stem cells
Genomic Conflicts, Health and Disease
(1) What are genomic conflicts and how are they
involved in disease?
(2) Main forms of genomic conflict
(a) Parent-offspring conflict
(b) Genomic-imprinting conflict
(c) Sexual conflicts
What is sexual conflict?
• Stems ultimately from differential investment by males
and females in reproduction (e.g. anisogamy)
• Can lead to different optima in males and females
for reproductive traits
fitness
females
males
trait value
 Both optima cannot simultaneously
be realised = sexual conflict
• Reinforced by
- multiple breeding episodes with different partners
(low shared interest in future reproductive bouts)
- low relatedness of mating pairs (usually 0)
Sexual conflict
• Selection for adaptations that favour each sex reaching its
optimum, despite the reduction in fitness this necessarily
causes in the other sex
• Followed by counter adaptation for ‘resistance’
=> sexually antagonistic coevolution
T. Chapman 2006, Curr. Biol.
Relevence to human health?
Think about these concepts when you think about sexual conflict
One arena of conflict: male ejaculate chemicals
AG
T
Internal
Male
Reproductive
System
T
AG
Accessory gland proteins (Acps)
Accessory glands
• SIMPLE PEPTIDES (<100 a/a)
• HORMONE-LIKE (200-400 a/a)
• LARGE GLYCOPROTEINS (>400 a/a)
Effects of Acps
Specific Acps:
•increase egg production
•decrease female receptivity after mating
•stimulate feeding
•essential for sperm storage
•process other Acps
•form a mating plug
Several Acps:
•increase success in sperm competition
•have antibacterial activity
Acps benefit males
• Acps increase egg laying, sperm storage,
success in sperm competition, and temporarily
prevent females from mating again
• in toto they act to increase male paternity,
and therefore benefit males
but Acps can reduce female fitness
1
0.9
Female survivorship
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
------ Full Acps
------ No Acps
 Non-mating control (1)
 Non-mating control (2)
0
1
3
5
7
9
11
13
15
17
19
21
23
25
27
29
31
Time (days)
(Chapman et al 1995)
33
35
Rapid evolution in reproductive proteins
•At least 11% of Acps evolve rapidly
e.g. Acp26Aa is fastest evolving gene in melanogaster genome (Ka/Ks
ratios >1)
•Significant polymorphism AND divergence
•Also rapid evolution in female D. melanogaster reproductive tract
proteins
•Lack of homologues, even between close relatives
•Recent evolution of Acp genes and high Acp gene turnover
Acps’s in humans:
the prostate
• Unique to mammals, analogous to
accessory glands in Drosophila
• Function is production of seminal fluid
• Consists of 30-50 sac-like glands connected to
excretory ducts
• Secretions play key roles in the fertilizing abilities of
the spermatozoa in the female reproductive tract
Prostate functional design and
evolution are essentially unstudied
• Is prostate size or form related to mating
system, among primates and other animals,
or among human races?
• What are the functions of the various
compounds secreted by the prostate and
seminal vesicles?
• Roles in human fertility, health?
Growth, Differentiation and Human Sexual
Dimorphism
• Mediated by androgens
• The main circulating androgen is testosterone
(produced by Leydig cells of the testis)
• Testosterone + 5α Reductase (enzyme)
 Dihydrotestosterone (DHT)
This enzyme is specific to the prostate and liver
* Androgens increase cell proliferation and inhibit apoptosis
Role of DHT in the Prostate
• Binds to androgen-receptor proteins
• Gets transported into the nucleus
• Initiates transcription of androgen
dependent genes
• Hence DHT controls the expression of
many proteins of the seminal fluid
Peptides and Proteins in Human Semen
Heaps and heaps of compounds of unknown function,
plus some known ones
•
PSA = Prostate Specific Antigen
- A biomarker for prostate cancer
- Protects the sperm of it’s male and slows
the sperm of others
• Semenogelin
- Two types (I and II)
- I- inhibits sperm motility and capacitation
- Both involved in the human semen coagulum
- Function in sperm competition in primates, evolves
faster in primate species with multiple mating known ones
• hCG human chorionic gonadotropin !
Evidence for adaptation in primate seminal proteins - though
evidence of function is sparse
Acps=accessory proteins (made in accessory glands)
protein in Drosophila seminal fluids
EFFECTS ON THE FEMALE in flies; what about in humanseffects on male and female?
• Increase
-oogenesis
-egg hatchability
-sperm storage
-ovulation
• Decrease
-receptivity to remating
-postmating viability
-sperm loss
-remating physically (are
a component of the
mating plug)
Prostate Cancer
• Involves a series of sequential mutations
• Mutations inhibit apoptosis and drive
cell proliferation
• Is testosterone-dependent (at least initially); breast cancer is
often estrogen-dependent
• Progression is mediated by genetic variation in the
androgen receptor gene
• Killer # 2 after lung cancer, surgery causes impotence and
incontinence
• Most men get it if they live long enough; starts to develop
in 20s - WHY?
Hypothesis for the evolution of
prostate cancer risk
• Strong selection for compounds that enhance male
reproductive function, even at a cost to females, and a cost
to males, especially in terms of cancer risk
* Seminal proteins evolve under sexual conflict - antagonistic
coevolution between genome as expressed in males and
genome as expressed in females - predicted to show
expression patterns associated with cancer
-> directly analogous to costs of Acp’s in flies
-> one key gene involved in prostate function, and
prostate cancer risk, is the androgen receptor
Androgen Receptor: protein that ‘activates’ effects of
testosterone. Extent of activation is mediated by number of
CAG microsatellite repeats
• MALES
Lower number of repeats - increased activation of
receptor and increased male fertility, but increased risk of
prostate cancer
Expect selection on males for fewer repeats (to a point)
• FEMALES
Lower number of repeats, higher rates of breast cancer
This is Evidence for Sexual Conflict
What about other prostate-expressed genes - does their
expression, activity affect cancer risk?
Main ways that sexual conflicts may
be involved in disease:
(1) Disruption of dynamic ‘tugs of war’ between
parties in conflict over reproductive resources
(as in parent - offspring, maternal genes-paternal genes,
and males - females) (IGF2-IGF2R in pregnancy)
(2) One party may ‘win’ a conflict, with costs imposed
on the other party (hCG? androgen receptor?)
(3) Strong selection and rapid evolution can result in
maladaptive byproducts, whereby strong selection for
one trait can result in maladaptation regarding other traits
(seminal proteins? androgen receptor?)
(4) Ongoing more or less direct physical, psychological
conflicts, costly to one or both parties