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Genetics and Prenatal Development






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

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Slide 1

Genetics and Prenatal Development

D. Messinger, Ph.D.

Messinger

Slide 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

Slide 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

Slide 4

Chromosomes

Ordered by karotyping

In vitro

Messinger

Slide 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

Slide 6

Detailed description

Messinger

Slide 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

Slide 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

Slide 9

Terms

  • Phenotype

    • Observable trait

      • “Phenotyping”

      • The broader phenotype (autism)

  • Genotype

    • Genetic pattern associated with the phenotype

Messinger

Slide 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

Slide 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

Slide 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

Slide 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

Slide 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

Slide 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

Slide 16

Sex-linked inheritance

  • Male’s “x” inherited from mother

    • Women are carriers

    • Males represented disproportionately in sex linked disorders

      • Color-blindness, hemophilia

Messinger

Slide 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

Slide 18

Twin Studies

Monozygotic vs Dizygotic: human studies of

genetic versus environment

Messinger

Slide 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

Slide 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

Slide 21

Sources of Variance in Behavior

  • Genetic (heritability)

  • Environmental

  • Gene x environment interaction

  • Error

Messinger

Slide 22

No genetic influence

Messinger

Slide 23

Genetic influence

Messinger

Slide 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

Slide 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

Slide 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

Slide 27

Questions

  • Why might adoption studies maximize estimates of genetic influence?

  • Can genetic effects increase with time?

    • How?

Messinger

Slide 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

Slide 29

Gene*Environment Interaction

Messinger

Slide 30

Gene * environment interactions

Gottlieb, 2003

Messinger

Slide 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

Slide 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

    Slide 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

    Slide 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

    Slide 35

    Which is better?

    Messinger

    Slide 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

    Slide 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

    Slide 38

    Methylation can mask the transcription of certain genes

    Messinger

    Slide 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

    Slide 40

    True or false?

    • Environmental factors for generation 1 can influence gene expression in generation 2

    Messinger


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