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Messinger Genetics and Prenatal Development D. Messinger, Ph.D.

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1 Messinger Genetics and Prenatal Development D. Messinger, Ph.D.

2 Quantitative and molecular genetics n Quantitative genetics: – Quantifies the strength of genetic and non-genetic factors n Genetics believed to play role in all traits n non-genetic influences also important n in gene-environment interactions, environment may have more/less impact on those who are/are not genetically susceptible n Molecular genetics: – Identification of specific genes involved in susceptibility – Some individual genes have been identified in liability to mental disorders; some also associated with variations in response to environmental hazards or medication Gangi

3 Messinger Class n What are the advantages (name some forms of genetic transmission) and disadvantages of thinking of genes as blueprints? n How do environmental and genetic influences interact during prenatal development (provide examples)? n What is the difference between transactional and a behavioral genetics approach to gene * environment interactions?

4 Messinger Basics n Genes – Bits of DNA in each cell – information on cell functioning & reproduction n Chromosomes – Larger groupings of DNA – All non-gamete cells have 23 pairs of chromosomes – Half of each pair came from each parent

5 Messinger Chromosomes In vitro Ordered by karotyping

6 Messinger Human genome project n identify the ~30,000 genes in human DNA, n determine the sequences of the 3 billion chemical base pairs that make up human DNA, n 99% (of nucleotide bases) are the same in all people

7 Messinger Detailed description

8 Messinger Disadvantages of the genes-as- blueprint metaphor n Genes are in a primarily liquid nucleus in a primarily liquid cell surrounded by other cells in a primarily liquid uterine environment – Without an “environment,” genes are just wound up nucleic acid n From a lump of jelly to an organism – How do genes actually work? – What is the role of “junk” DNA?

9 Messinger Genomes to Life Project - Proteomics n Identify the protein machines that carry out critical life functions and the gene regulatory networks that control these machines

10 Messinger Terms n Phenotype – Observable trait n “Phenotyping” n The broader phenotype (autism) n Genotype – Genetic pattern associated with the phenotype

11 Messinger Polygenic inheritance – not blue- print inheritance - is the rule n Multiple genes influence most traits n Sign of polygenic inheritance is range in phenotype rather than either/or – skin/eye/hair color, height, baldness, personality – Reaction Range – Potential variability in expression of a trait n Such traits may also be susceptible to environmental influence

12 Messinger How are genes a blueprint? n “The DNA sequence (e.g., ATTCCGGA)... spells out the exact instructions required to create a particular organism with its own unique traits.” n A metaphor which describes cases in which there is a specific correspondence between genotype and phenotype

13 Messinger Blueprint-like modes of genetic transmission n Dominant-recessive – Single gene or Mendellian n Specific genetic defects can be deadly or disabling n sickle cell, phenylkitenuria (but see Knox & Messinger, 1958), etc.Knox & Messinger, 1958 n Sex-linked (23rd chromosome)

14 Messinger Dominant-Recessive Inheritance n Traits are transmitted as separate units n Autosomes - 22 pairs – Non-sex chromosomes – One pair from each parent n When 2 competing traits are inherited – Only 1 trait is expressed n Dominant trait n Recessive trait

15 Messinger Dominant-Recessive Inheritance Traits are transmitted as separate units 25% risk of inheriting a “double-dose” of r genes which may cause a serious birth defect 25% chance of inheriting two N’s thus being unaffected 50% chance of being a carrier as both parents are

16 Messinger Sex-linked inheritance n 23rd chromosomal pair n Male = XY (Missing an arm) – one Y branch not matched – so allele on corresponding X branch is expressed n Female = XX – each branch is matched

17 Messinger Sex-linked inheritance n Male’s “x” inherited from mother – Women are carriers – Males represented disproportionately in sex linked disorders n Color-blindness, hemophilia

18 Messinger Behavioral genetics n The influence of genetic and environmental factors be distinguished and the influence of each can be quanitified using behavioral genetic methods (Plomin)

19 Messinger Twin Studies Monozygotic vs Dizygotic: human studies of genetic versus environment

20 Messinger Twin studies n Identical (MZ) twins share 100% of their genes – genetic duplicates. n Fraternal (DZ) twins share 50% of their genes – on average n Both types of twins have similar environments... n Greater behavioral similarity of identical twins indexes greater genetic influence

21 Modeling differences between correlations Messinger n A (additive genetics) C (common environment) and E (unique environment); ACE Model. n The correlation we observe between MZ twins provides an estimate of A + C. n Dizygous (DZ) twins have a common shared environment, and share on average 50% of their genes: so the correlation between DZ twins is a direct estimate of ½A + C. n r mz = A + C r dz = ½A + C Where r mz and r dz are simply the correlations of the trait in MZ and DZ twins respectively. n Twice difference between MZ and DZ twins gives us A: the additive genetic effect n C is simply the MZ correlation minus our estimate of A. The random (unique) factor E is estimated directly by how much the MZ twin correlation deviates from 1. n difference between the MZ and DZ correlations is due to a halving of the genetic similarity… n So additive genetic effect 'A' is simply twice the difference between the MZ and DZ correlations: n A = 2 (r mz – r dz ) As the MZ correlation reflects the full effect of A and C, E can be estimated by subtracting this correlation from 1 n E = 1 – r mz Finally, C can be derived: n C = r mz – A = 2 r dz – r mz

22 Messinger Sources of Variance in Behavior n Genetic (heritability) n Environmental n Gene x environment interaction n Error

23 Messinger No genetic influence

24 Messinger Genetic influence

25 Messinger “Most, if not all, reliably measured psychological traits, normal and abnormal, are substantively influenced by genetic factors.” Bouchard, T. J. (2004). "Genetic Influence on Human Psychological Traits: A Survey." Current Directions in Psychological Science 13(4): 148-151.

26 Messinger

27 Estimates of genetic and environmental influence n Proportional in samples – Greater environmental variation n Will minimize genetic variation – E.g. Poverty – Greater genetic variation n Will minimize environmental variation – E.g. Downs Syndrome

28 Messinger Environmental effects n Previously modeled but not measured n Now parental monitoring, neighborhood deprivation account for small (2-5%) of environmental variation – What else should we be measuring?

29 Messinger Gene * Environment interactions – Genetic effects on alcohol use are greater in non- religious than religious households n Why? – Genetic effects on seeking specific environments – n Identical twins find similar friends n Identical twins treated more similarly (or differently) than fraternal twins?

30 Messinger Questions n Why might adoption studies maximize estimates of genetic influence? n Can genetic effects increase with time? – How?

31 Messinger Transactional perspective on gene*environment interface n “It is not nature vs. nurture, but the interaction of nature and nurture that drives development.” Urie Bronfrenbrenner

32 Messinger Gene*Environment Interaction

33 Messinger Gottlieb, 2003 Gene * environment interactions

34 Messinger Demonstrates importance of…G*E

35 Messinger “What will it take to make behavioral genetics truly developmental?” n An analysis of the bi-directional relations from gene action to the external environment over the life course, including the prenatal period. Gottlieb, G. (2003 ). Human Development 46(6): 337-355.

36 Messinger Transactional model

37 Genes in Context Champagne & Mashoodh, 2009 n Gene-by-environment effects – Combining molecular biology & study of behavior – Examples: n Cooper & Zubek, 1958 – bred “maze-dull” and “maze- bright” rats, reared in “enriched” or “impoverished” environments n Prediction of behavior should incorporate environmental context Gangi n seroton in transpo rter gene and stressfu l life events interact to predict depress ion

38 Measured Gene-Environment Interactions and Mechanisms Promoting Resilient Development. (Kim-Cohen & Gold, 2009) n Individuals carrying “protective” allele have lower levels of psychopathology than those that posses the “vulnerable” allele n In maltreated children: – “short” (low) serotonin transporters (5-HTT gene) only see greater risk for depression in high-stress conditions. – Dunedin Longitudinal Study (Caspi et al., 2003) – No effect in individuals not exposed to risk – (Caspi & Moffitt, 2006) – Replication debate Fernandez – low vs. high levels of monoami ne oxidase (MAOA) enzyme expressio n

39 Contextual Determinants of Gene Function n Gene = sequence of DNA n Transcription = enzymes “read” DNA n Environment around DNA makes it possible to “read” DNA n Epigenetic – “in addition to genetic” – Influences that determine expression without altering the DNA Gangi

40 Messinger n Several epigenetic mechanisms alter gene activity in neurons, with potentially important effects on brain function and behavior. n Histone acetylation tends to promote gene activity, n whereas histone methylation and DNA methylation tend to inhibit it.

41 Which is better? Messinger

42 Environmental Influences on Gene Activity n In rodents: – Low maternal care  elevated methylation – Prenatal exposure to chronic stress  increased methylation n Less nurturing mothering leads to poorer stress response in rat pups n Fewer corticosterone receptors n Linked to DNA methylation n Enzymes reverse methylation, improve receptor numbers – Szyf & Meany (2004) Gangi

43 Epigenetics in Rodents n Champagne’s extension to later mothering – Less mothering attention -> Greater methylation n Less mothering attention in the next generation n Roth and Sweatt (2009) – Stressed mothers spend less time nurturing – Lower BDNF hormone -> Greater methylation - > Lower neural growth n Linked to anxiety in mice, responds to antidepressants n Miller and Sweatt (2007)- Inhibition of methylation  detrimental to memory n Nestler et al. (2010) Cocaine exposure – Higher acetylation and methylation of histones n Stimulates reward circuitry Mattson

44 Methylation can mask the transcription of certain genes Messinger

45 Epigenetics in Humans – Antenatal depression and anxiety  higher methylation – Suicide victims  elevated methylation in hippocampus Szyf & McGowan (2009) n More methyl groups in glucocorticoid receptor genes of abused – Umbilical cord blood, higher methylation and higher later cortisol, increased susceptibility to stress (Oberlander et al., 2008) n Greater discordance in gene expression in older twins – associated with greater differences in methylation – The Seductive Allure of Behavioral Epigenetics. Miller (2010) Miller Mattson n Hard to get brain tissue  indirect sampling – Twin studies, particularly Fraga's (2005), indicate genetic variation between young and old monozygotic twins – Social interactions regulate gene expression n Different tissues, different ways n Need a directed search rather than just epigenetic flags

46 True or false? n Environmental factors for generation 1 can influence gene expression in generation 2 Messinger

47 Developmental Interpretation n Brain structure & function in interaction with stress vs. current status of serotonin functioning in the adult brain (Brown & Harris, 2008) Epistasis : gene-gene interaction n Individuals may still be resilient event if they posses a “risk” gene (Cicchetti et al., 2007) Relationship Effect n Supportive relationship with an adult protected maltreated children from developing depression (Kaufman et al., 2006) Fernandez

48 Environmental “Pathogen” n High depressive symptoms with carriers of low-activity MAOA allele n Effects of multiple types of maltreatment n “Resilience” can be due to variability in exposure to environmental risk factors – Accuracy of risk exposure (Cicchetti, Rogosch & Sturge-Apple, 2007) Fernandez

49 Interventions n Pharmacological vs. psychosocial Imaging genomics n effect on emotion processing in psychiatrically healthy adults – exaggerated amygdala response to fearful or angry faces (Caspi & Moffitt, 2006; Viding,Williamson, & Hariri, 2006) Limitations n Correlation or quasi-experimental designs; no causality – Intervention studies: prediction of treatment efficacy Fernandez

50 Future Directions Absence of psychopathology vs. competent functioning Effects of genes n Supportive caregiving (Bakermans-Kranenburg, et al., 2008) n Relationship between breast feeding and IQ scores (Caspi et al., 2007) n No single allele is risk-inducing under all contexts (Belsky et al., 2007) Fernandez

51 What Can Methylation Mean for Rats? Weaver (2004) - GR Gene in Rodents - Drugs introduced in adult rats targeting this gene can affect stress response, reducing response to the level of rats who received low maternal care. In addition to stress effects during pregnancy, rodents place on methyl rich diets can cause an effect in color expression with the Agouti mutation. Matson Champagne & Mashoodh (2009)

52 Developmental Processes n For developmental programming: dependent on having experiences within a broad range (experience expectant), also provides adaptation to environments experienced (experience- adaptive) n Research should consider diversity of causal processes, including genetic, environmental, and developmental processes Gangi

53 Messinger n Nature – genetics – Genes as blueprint n Nurture – environment – Infinite malleability n Genes, environment, and their interaction accounting for outcome? n Gene-environment transaction? Back to developmental models Who believes in?

54 Gene-environment interactions (G x E) n Environmental risks that interact with genes to predict vulnerability and resilience n Measured Gene-Environment Interactions and Mechanisms Promoting Resilient Development. (Julia Kim-Cohen & Andrea L. Gold, 2009) Fernandez

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