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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

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Genetics and prenatal development l.jpg

Genetics and Prenatal Development

D. Messinger, Ph.D.

Messinger


Quantitative and molecular genetics l.jpg
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


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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


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Chromosomes

Ordered by karotyping

In vitro

Messinger


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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



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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


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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


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Terms

  • Phenotype

    • Observable trait

      • “Phenotyping”

      • The broader phenotype (autism)

  • Genotype

    • Genetic pattern associated with the phenotype

Messinger


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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


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How are genes a blueprint? the rule

  • “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


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Blueprint-like the rulemodes 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


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Dominant-Recessive Inheritance the rule

  • 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


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Dominant-Recessive Inheritance the rule

  • 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


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Sex-linked inheritance the rule

  • 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


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Sex-linked inheritance the rule

  • Male’s “x” inherited from mother

    • Women are carriers

    • Males represented disproportionately in sex linked disorders

      • Color-blindness, hemophilia

Messinger


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Behavioral genetics the rule

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

Messinger


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Twin Studies the rule

Monozygotic vs Dizygotic: human studies of

genetic versus environment

Messinger


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Twin studies the rule

  • 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


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Modeling differences between correlations the rule

  • 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


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Sources of Variance in Behavior the rule

  • Genetic (heritability)

  • Environmental

  • Gene x environment interaction

  • Error

Messinger


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No genetic influence the rule

Messinger


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Genetic influence the rule

Messinger


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“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


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Estimates of genetic and environmental influence normal and abnormal, are substantively influenced by genetic factors.”

  • 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


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Gene * Environment interactions normal and abnormal, are substantively influenced by genetic factors.”

  • 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


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Questions normal and abnormal, are substantively influenced by genetic factors.”

  • Why might adoption studies maximize estimates of genetic influence?

  • Can genetic effects increase with time?

    • How?

Messinger


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Transactional perspective on gene*environment interface normal and abnormal, are substantively influenced by genetic factors.”

  • “It is not nature vs. nurture, but the interaction of nature and nurture that drives development.” Urie Bronfrenbrenner

Messinger


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Gene*Environment Interaction normal and abnormal, are substantively influenced by genetic factors.”

Messinger


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Gene * environment interactions normal and abnormal, are substantively influenced by genetic factors.”

Gottlieb, 2003

Messinger


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“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


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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


    Contextual determinants of gene function l.jpg
    Contextual Determinants of Gene Function Promoting Resilient Development

    • 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


    Slide34 l.jpg

    Messinger


    Which is better l.jpg
    Which is better? neurons, with potentially important effects on brain function and behavior.

    Messinger


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    Environmental Influences on Gene Activity neurons, with potentially important effects on brain function and behavior.

    • 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


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    Epigenetics in Rodents neurons, with potentially important effects on brain function and behavior.

    • 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


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    Methylation can mask the transcription of certain genes neurons, with potentially important effects on brain function and behavior.

    Messinger


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    Epigenetics in Humans neurons, with potentially important effects on brain function and behavior.

    • 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


    True or false l.jpg
    True or false? neurons, with potentially important effects on brain function and behavior.

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

    Messinger


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