![Gene-Endoenvironment Interaction
DRD4 - Long Allele
– Novelty/Sensation Seeking
– Attention Problems/Aggression
– Susceptibility to Parenting
EEG Asymmetry
– Left Frontal – “Easy”
Temperament
– Right Frontal – “Negative
Reactive” Temperament
– Schmidt, Fox, Perez-Edgar & Hamer
(2009)
Mattson
"Long" versions of polymorphisms
are the alleles with 6 to 10 repeats.
7R appears to react less strongly to
dopamine molecules.[8]
http://en.wikipedia.org/wiki/Dopamine_recept
or_D4](https://image.slidesharecdn.com/environandgenetics-240218214547-dab1b77a/85/environ-and-genetics-in-general-aspects-ppt-28-320.jpg)
![“[S]urgery-induced weight loss was
associated with a dramatic
remodeling of sperm DNA
methylation, notably at genetic
locations implicated in the central
control of appetite.”
Messinger
Donkin, I., Versteyhe, S., Ingerslev, L. R., Qian, K., Mechta
M., Nordkap, L., . . . Barres, R. (2015). Obesity and
Bariatric Surgery Drive Epigenetic Variation of
Spermatozoa in Humans. Cell Metab. doi:
10.1016/j.cmet.2015.11.004](https://image.slidesharecdn.com/environandgenetics-240218214547-dab1b77a/85/environ-and-genetics-in-general-aspects-ppt-41-320.jpg)
environ and genetics in general aspects.ppt
- 1. Messinger Genetics and Prenatal Development D. Messinger, Ph.D.
- 2. Messinger Basics Genes – Sequences 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 In vitro Ordered by karotyping
- 3. Messinger Human genome project identify the ~30,000 genes in human DNA – Genetic sequences that make proteins – the exome 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
- 5. Messinger Proteomics Identify the protein machines that carry out critical life functions and the gene regulatory networks that control these machines
- 6. Messinger 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
- 7. Messinger Blueprint-like modes 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)
- 8. Messinger 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
- 9. Messinger Dominant-Recessive Inheritance Normal (NN) Carrier (Nr) Carrier (Nr) Affected (rr) Carrier Father (Nr) + Carrier Mother (Nr) 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
- 10. Messinger 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 Male X inherited from mom – Women are carriers – Males disproportionately represented in sex linked disorders Color-blindness, hemophilia
- 11. Rare variants rare variant mutations with a minor allele frequency < 1% associated with ASD – CHD8, CNTNAP2, NLGN4, NRXN1, and CNTN4 But no specific gene accounts for a majority of ASD cases – Among siblings both diagnosed with ASD, most do not share the same ASD risk genes, Messinger
- 12. Common variants polymorphisms occurring in > 1–2% of the population may comprise a substantial portion of the risk heritability of ASD However, identified common variants that in combination or alone influence ASD susceptibility have not been well replicated focus on the genetic basis of behaviors relevant to ASD may be productive Messinger
- 13. Messinger Behavioral genetics The influence of genetic and environmental factors be distinguished and the influence of each can be quanitified using behavioral genetic methods (Plomin)
- 14. Messinger Twin Studies Monozygotic vs Dizygotic: human studies of genetic versus environment
- 15. Messinger 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
- 16. Messinger Sources of Variance in Behavior Genetic (heritability) Environmental Gene x environment interaction Error
- 17. A (additive genetics) C (common environment) and E (unique environment)—ACE Model Messinger http://en.wikipedia.org/wiki/Twin_study Correlation between MZ twins provides an estimate of A + C : rmz = A + C Dizygous (DZ) twins share common environment, & average of 50% of genes: – the correlation between DZ twins is an estimate of ½A + C: rdz = ½A + C Twice difference between MZ and DZ twins gives us A: additive genetic effect C is simply the MZ correlation minus our estimate of A. The random (unique) factor E is estimated by how much the MZ twin correlation deviates from 1. E = 1 – rmz difference between the MZ and DZ correlations is half the genetic similarity… 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 C = rmz – A = 2 rdz – rmz
- 19. Messinger Genetic influence 0 10 20 30 40 50 60 Behavior Similarity Correlation Dizygotic Monozygotic Genetic Relatedness Twin 1 Twin 2
- 20. Messinger 2 perspectives on gene*environment interface Transactional – “It is not nature vs. nurture, but the interaction of nature and nurture that drives development.” Urie Bronfrenbrenner (what we just heard) Quantitative – The influence of genetic and environmental factors be distinguished and the influence of each can be quanitified using behavioral genetic methods (Plomin)
- 21. 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 Psychologi cal Traits: A Survey." Current Directions in Psychologi cal Science 13(4): 148- 151.
- 22. Messinger 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
- 23. Messinger 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?
- 25. Messinger “What will it take to make behavioral genetics truly developmental?” 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.
- 26. Initial Evidence: Gene * Environment Interaction Caspi et al., 2003
- 28. Gene-Endoenvironment Interaction DRD4 - Long Allele – Novelty/Sensation Seeking – Attention Problems/Aggression – Susceptibility to Parenting EEG Asymmetry – Left Frontal – “Easy” Temperament – Right Frontal – “Negative Reactive” Temperament – Schmidt, Fox, Perez-Edgar & Hamer (2009) Mattson "Long" versions of polymorphisms are the alleles with 6 to 10 repeats. 7R appears to react less strongly to dopamine molecules.[8] http://en.wikipedia.org/wiki/Dopamine_recept or_D4
- 29. DRD4 by Asymmetry Mattson – Susceptibility to asymmetry in Soothability Attention Difficulties – symmetry unrelated to DRD4 – Complex Gene-Gene Interaction? Schmidt, Fox, Perez-Edgar & Hamer (2009)
- 30. Dopaminergic genes & joint attention Gangi et al., 2016
- 31. Genes influence relation between parenting and temperament • 18-21 month olds • DRD4 48 (7-repeat allele) “long” allele increased sensitivity to environmental factors such as parenting. • Lower quality parenting higher sensation seeking. • Higher quality parenting lower sensation seeking • Parenting quality interacts with genetic variation in dopamine receptor D4 to influence temperament in early childhood Sheese BE, et al. Dev Psychopathol 2007 19(4):1039-46 Messinger & Henderson 46
- 32. A Sekar et al. Nature 1–6 (2016) doi:10.1038/nature16549 C4 structures, C4A expression, and schizophrenia risk Schizophrenia risk from complex variation of complement component 4 schizophrenia is increased with inheritance of specific variants in a gene related to "synaptic pruning“ http://www.sciencedaily.com/rel eases/2016/01/160127141400.ht m risk
- 33. Hmmm… “Mothers who were pregnant during a 1944 famine in the Netherlands, for example, were more likely to have children—and grandchildren—prone to heart disease, diabetes, and obesity. Female mice that are underfed during pregnancy also give birth to pups that are more likely to develop diabetes—and their male offspring have epigenetic changes in their sperm. The offspring of those males are also prone to diabetes. Male rats that are overfed, when mated with healthy females, also had offspring that were prone to developing diabetes.” • http://www.sciencemag.org/news/2015/12/weight-gain-and-loss-can-alter-men-s-sperm Messinger
- 35. Environmental Influences on Gene Activity In rodents: – Prenatal exposure to chronic stress hi methylation – Low maternal care high 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
- 36. How can an organism have different cell types yet one genome? “The idea that DNA function could be stably diversified without changing the sequence comes from the study of cellular differentiation during embryonal development.” (Szyf & Bick, 2012) Messinger
- 37. Global Epigenomic Reconfiguration During Mammalian Brain Development (Lister et al., 2013) • DNA methylation is a stable covalent modification that persists in post-mitotic cells throughout their lifetime, helping define their cellular identity Types 1. mCG 2. mCH (where H = A, C, or T)
- 38. DNA transcription: the process of DNA being read by an enzyme called RNA polymerase > leading to the production of mRNA > which is then translated into a protein DNA methylation: one type of epigenetic mechanism; reduces the accessibility of DNA and can lead to “silencing” of the gene Epigenetic influences do NOT alter the sequence of DNA (Champagne & Mashoodh, 2009; Syzf & Bick, 2012) Rumper
- 39. Messinger Epigenetic mechanisms Histone acetylation tends to promote gene activity Histone methylation and DNA methylation tend to inhibit it.
- 40. DNA methylation adaption are system wide and involve multiple gene circuitries Messinger
- 41. “[S]urgery-induced weight loss was associated with a dramatic remodeling of sperm DNA methylation, notably at genetic locations implicated in the central control of appetite.” Messinger Donkin, I., Versteyhe, S., Ingerslev, L. R., Qian, K., Mechta M., Nordkap, L., . . . Barres, R. (2015). Obesity and Bariatric Surgery Drive Epigenetic Variation of Spermatozoa in Humans. Cell Metab. doi: 10.1016/j.cmet.2015.11.004
- 42. 1. CH methylation accumulates in neurons through early childhood & adolescence – becoming the dominant form of DNA methylation in mature human neurons Widespread methylome reconfiguration during fetal to young adult development is coincident with synaptogenesis. Demonstrates large-scale reconfiguration of neuronal epigenome!
- 43. Background Maternal depression can lead to negative child outcomes Through what mechanisms does maternal depression affect children’s genetic expression? Greater Methylation? NR3C1 fewer receptors present for binding 11B-HSD-2 no longer converts maternal cortisol into cortisone Maternal Sensitivity and Responsiveness? Previous studies examined the process in rodents Conradt et al., 2016 Rumper
- 44. Maternal Sensitivity and Responsiveness Maternal depressive symptoms Infant’s DNA Methylation Aim 1 Conradt et al., 2016 Rumper
- 45. Maternal Sensitivity and Responsiveness Maternal depressive symptoms Infant’s cortisol levels Aim 2 Conradt et al., 2016 Rumper
- 46. Maternal Sensitivity and Responsiveness Maternal depressive symptoms Infant’s cortisol levels Aim 3 Infant’s cortisol levels Conradt et al., 2016 Rumper
- 47. Methods Mother: Anxiety Depression Sensitivity and Responsiveness: Acceptance /Nondemanding Responsiveness/Appropriate Touch Infant: Cortisol x 3 Buccal Sample Collection Conradt et al., 2016 Rumper
- 48. Conradt et al., 2016 Results Rumper
- 49. Conradt et al., 2016 Rumper Results
- 50. Discussion Questions What is the practical significance of these findings? Methods? Cortisol reliable? Thoughts about other maternal behaviors that should be measured? Why might there be a positive correlation between methylation of 11B-HSD CpG1 and accepting/nondemanding? What are other maternal behaviors that may better align with “licking and grooming” behaviors in rodents? Future Directions? Conradt et al., 2016 Rumper
- 51. Epigenetic modulation? Brown 2017 Parenting Child adjustment Mechanisms? Societal factors: amount & quality of child care Parental stress and mental health Neurobiology: low stress reactivity; PFC function
- 52. Parental Acceptance-Rejection Questionnaire (PARQ) (with and without outliers) Brown 2017
- 53. Behavior Assessment System for Children – College Version (BASC-CV) Brown 2017
- 55. A word on identity Messinger 1.Amy M. Boddy, Angelo Fortunato, Melissa Wilson Sayres, Athena Aktipis. Fetal microchimerism and maternal health: A review and evolutionary analysis of cooperation and conflict beyond the womb.BioEssays, 2015; DOI: 10.1002/bies.2015000 59
- 56. Parent-of-Origin DNA Methylation Dynamics during Mouse Development Copyright © 2016 The Authors Terms and Conditions Using a recently established DNA methylation reporter, Stelzer et al. study parent- specific methylation dynamics at the Dlk1-Dio3 imprinted control region. Reporter activity uncovered tissue- and cell- dependent signatures through mouse development and in adult tissues, suggesting that dynamic methylation changes regulate imprinted gene expression in pre- and postnatal animals.