Genetics and Prenatal Development

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

2. Quantitative and molecular genetics • Quantitative genetics: • Quantifies the strength of genetic and non-genetic factors • Genetics believed to play role in all traits • non-genetic influences also important • in gene-environment interactions, environment may have more/less impact on those who are/are not genetically susceptible • 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. Basics • Genes • Bits of DNA in each cell • information on cell functioning & reproduction • Chromosomes • Larger groupings of DNA • All non-gamete cells have 23 pairs of chromosomes • Half of each pair came from each parent Messinger

4. Chromosomes Ordered by karotyping In vitro Messinger

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

6. Detailed description Messinger

7. Disadvantages of the genes-as-blueprint metaphor • 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 • From a lump of jelly to an organism • How do genes actually work? • What is the role of “junk” DNA? Messinger

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

9. Terms • Phenotype • Observable trait • “Phenotyping” • The broader phenotype (autism) • Genotype • Genetic pattern associated with the phenotype Messinger

10. Polygenic inheritance – not blue-print inheritance - is the rule • Multiple genes influence most traits • 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 • Such traits may also be susceptible to environmental influence Messinger

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

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

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

14. 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 Messinger

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

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

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

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

19. Twin studies • Identical (MZ) twins share 100% of their genes • genetic duplicates. • Fraternal (DZ) twins share 50% of their genes • on average • Both types of twins have similar environments . . . • Greater behavioral similarity of identical twins indexes greater genetic influence • http://www.psych.umn.edu/psylabs/mtfs/special.htm Messinger

20. Modeling differences between correlations • A (additive genetics) C (common environment) and E (unique environment); ACE Model. • The correlation we observe between MZ twins provides an estimate of A + C . • 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 . • rmz = A + Crdz = ½A + C Where rmz and rdz are simply the correlations of the trait in MZ and DZ twins respectively. • Twice difference between MZ and DZ twins gives us A: the additive genetic effect • 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. • difference between the MZ and DZ correlations is due to a halving of the genetic similarity… • So additive genetic effect 'A' is simply twice the difference between the MZ and DZ correlations: • A = 2 (rmz – rdz) As the MZ correlation reflects the full effect of A and C, E can be estimated by subtracting this correlation from 1 • E = 1 – rmz Finally, C can be derived: • C = rmz – A = 2 rdz – rmz http://en.wikipedia.org/wiki/Twin_study Messinger

21. Sources of Variance in Behavior • Genetic (heritability) • Environmental • Gene x environment interaction • Error Messinger

22. No genetic influence Messinger

23. Genetic influence Messinger

24. “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 Science13(4): 148-151. Messinger

25. Estimates of genetic and environmental influence • Proportional in samples • Greater environmental variation • Will minimize genetic variation • E.g. Poverty • Greater genetic variation • Will minimize environmental variation • E.g. Downs Syndrome Messinger

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

27. Questions • Why might adoption studies maximize estimates of genetic influence? • Can genetic effects increase with time? • How? Messinger

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

29. Gene*Environment Interaction Messinger

30. Gene * environment interactions Gottlieb, 2003 Messinger

31. “What will it take to make behavioral genetics truly developmental?” • 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 Development46(6): 337-355. Messinger

32. Measured Gene-Environment Interactions and Mechanisms Promoting Resilient Development. (Kim-Cohen & Gold, 2009) • Individuals carrying “protective” allele have lower levels of psychopathology than those that posses the “vulnerable” allele • 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 monoamine oxidase (MAOA) enzyme expression

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

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

35. Which is better? Messinger

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

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

38. Methylation can mask the transcription of certain genes Messinger

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

40. True or false? • Environmental factors for generation 1 can influence gene expression in generation 2 Messinger