Genomic Conflicts, Health and Disease What are genomic conflicts and

1. Genomic Conflicts, Health and Disease What are genomic conflicts and how are they involved in health and disease? (2) Main forms of genomic conflict Parent-offspring conflict (b) Genomic-imprinting conflict (c) Sexual conflict

2. The logic & dynamics of genomic evolutionary conflict, in relation to health and disease Frank & Crespi 2011, PNAS

3. (a) Parent-offspring conflict is due to higher relatedness to self/own offspring than to sib/nieces, nephews r = 1/2 r = 1/4

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?

5. 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 of 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?

6. 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 Offspring 1’ s fitness A 3(.5) = 1.5* 0.5 + 2(.5)(.5)=1.0 B 2(.7) = 1.4 0.7 + 1(.5)(.7)=1.05* C 1(.9) = 0.9 0.9 + 0(.5)(0.9)=0.9 Units->Survival 33->.5 50->.7 100->.9

7. 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

8. 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

9. Conceptus @ 9 days old

10. 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 Mother and baby Both ‘want’ pregnancy maintained Baby ‘wants’ pregnancy maintained, mother does not CONFLICT 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

11. luteinizing hormone progesterone Pregnancy is maintained via the production of LH and LH’s stimulation of progesterone (P) production. anterior pituitary Temporary endocrine structure, from ovarian follicle corpus luteum uterus

12. progesterone hCG bypasses this pathway and stimulates the corpus luteum to produce progesterone and by the 8th week of pregnancy, produces enough P to sustain pregnancy on its own. anterior pituitary luteinizing hormone human chorionicgonadotropin corpus luteum placenta uterus

13. hCG bypasses this pathway and stimulates the corpus luteum to produce progesterone and by the 8th week of pregnancy, produces enough progesterone to sustain pregnancy on its own. anterior pituitary luteinizing hormone chorionicgonadotropin corpus luteum progesterone placenta progesterone uterus

14. Conflicts over food for the growing fetus: Invasion of the placenta into the uterine wall. Allows fetus to prevent cut-off 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

15. “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

16. MAIN STAGES OF PARENT-OFFSPRING CONFLICT: 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

17. How parent-offspring conflicts contribute to disease 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

18. 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-imprintingconflict 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 dad from mom

19. Imprinted gene expression compared to biallelic gene expression

20. How imprinting works, across the life cycle

21. Asymmetries in parentalinvestment are high Why imprinting has evolved, in placental mammals: • 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

22. Evolution of genomic imprinting in placental mammals under multiple paternity and high maternal investment: Paternal gene Maternal gene Relatedness of paternal gene in offspring, to siblings, goes from 0.5 to 0 as we go from monogamy to polygamy 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

23. Evolution of genomic imprinting in placental mammals under multiple paternity and high maternal investment: Paternal gene Maternal gene Relatedness of paternal gene in offspring, to siblings, goes from 0.5 to 0 as we go from monogamy to polygamy EXTREME CASE: Relatedness of maternal gene in offspring, to siblings, is always 0.5 Mum’s Brood

24. IMPRINTED GENES 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)

25. 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:

26. Imprinted genes are ‘master regulators’ of placentation: they control growth and differentiation

27. CONFLICT THEORY OF IMPRINTING -> abundant support from empirical studies of imprinted genes and growth, in mice and humans IGF2-IGF2R (Haig & Graham 1991 Cell) (2) CDKN1C (Andrews et al. 2007 BMC Dev Biol) (3) GRB10 (Charalambous et al. 2003 PNAS) Beckwith- Wiedemann Syndrome Silver- Russell syndrome 2 doses IGF2 Mighty mouse Normal sized human 1 dose IGF2 0 doses IGF2

29. Effects of alterations to imprinted genes on the placenta in mice KNOCKOUTS

30. *

31. Dysregulation of imprinted genes in the placenta is an important cause of intra-uterine growth restriction (IUGR) in humans Imprinting Placentation

32. Imprinting can cause genetic disorders, if both chromosomes are inherited from same parent

33. 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

34. 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

35. Chimeric mouse brain

36. 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

37. 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

38. 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)

39. Angelman: paternal additions and/or maternal deletions on chromosome 15q11-13 Prader-Willi:maternal additions and/or paternal deletions on chromosome 15q11-13 Oppositely-imprinted disorders of the brain: Prader-Willi & Angelman syndromes

40. prolonged suckling frequent crying hyper-active/sleepless low pleasure threshold severe retardation: no language autism poor suckling weak crying inactive/sleepy high pain threshold affective psychosis in adults AngelmanPrader-Willi Every mother’s worst fear, as regards behaviour of a child Complacent, easy on mom

41. 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

42. 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

43. Main mechanisms whereby alterations to imprinted genes promote cancer development

45. BWS = Beckwith- Wiedemann syndrome

46. Alterations to genomic imprinting alter the properties of embryonic stem cells

47. Genomic Conflicts, Health and Disease 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

48. 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 • Reinforced by • - multiple breeding episodes with different partners (low shared interest in future reproductive bouts) • - low relatedness of mating pairs (usually 0) fitness females males Leigh Simmons trait value •  Both optima cannot simultaneously • be realised = sexual conflict

49. 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

50. T. Chapman 2006, Curr. Biol. Relevence to human health?