messinger genetics and prenatal development d. messinger, ph.d

Messinger

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 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

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Chromosomes

In vitro Ordered by karotyping

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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

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Detailed description

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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?

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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

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Terms

Phenotype– Observable trait

“Phenotyping” The broader phenotype (autism)

Genotype– Genetic pattern associated with the phenotype

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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

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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

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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)

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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

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Dominant-Recessive Inheritance

Norm al(NN )

Carrier(Nr)

Carrier(Nr)

Affected(rr)

Carrier Father (Nr)+

Carrier M other (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

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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

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Sex-linked inheritance

Male’s “x” inherited from mother– Women are carriers– Males represented disproportionately in sex linked

disorders Color-blindness, hemophilia

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Behavioral genetics

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

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Twin Studies

Monozygotic vs Dizygotic: human studies ofgenetic versus environment

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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

Modeling differences between correlations

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http://en.wikipedia.org/wiki/Twin_study

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 + C rdz = 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

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Sources of Variance in Behavior

Genetic (heritability) Environmental Gene x environment interaction Error

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No genetic influence

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Genetic influence

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Dizygotic Monozygotic

Genetic Relatedness

Twin 1Twin 2

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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 Science 13(4): 148-151.

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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

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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?

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Questions

Why might adoption studies maximize estimates of genetic influence?

Can genetic effects increase with time?– How?

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Transactional perspective on gene*environment interface “It is not nature vs. nurture, but the

interaction of nature and nurture that drives development.” Urie Bronfrenbrenner

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Gene*Environment Interaction

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Gottlieb, 2003Gene * environment interactions

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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 Development 46(6): 337-355.

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

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

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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.

Which is better?

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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)

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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

Methylation can mask the transcription of certain genes

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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 (Oberlander et al., 2008)

Greater discordance in gene expression in older twins – associated with greater differences in methylation

– The Seductive Allure of Behavioral Epigenetics. Miller (2010)

Mattson

True or false?

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

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