Foundations of Genetic Research: A PrimerHow can something so tiny make such a big difference?

Rebecca A. LundwallPsychology Department

Brigham Young University

Just a Few Branches of Genetics Classical (Mendelian) genetics

Developmental genetics Evolutionary genetics Genomics (sequences) Medical genetics

Population genetics◦ Quantitative genetics

Genetic epidemiology Psychiatric genetics Behavioral genetics

◦ Molecular genetics

HeterogeneityIndividuals are different in behavioral as well as physical traits.Some of the differences might be influenced by genes.

Behavioral GeneticsThe attempt to establish heritability: that any genes influence a particular behavior. Initial approaches often use twin and/or adoption studies.

Behavior Genetics

Twin & Adoption Studies

Assess the impact of nature & nurture:

study traits of siblings vs. identical twins

see if siblings vary more than twins

Fraternal and Identical TwinsFraternal “twins” from separate eggs are not any more genetically alike than other siblings.

Identical twin: Same sex only

Fraternal twin: Same or opposite sex

Study the traits of identical twins as they grow up together or separately (Minnesota Twin Family Study).

Identical vs. Fraternal TwinsStudies of twins in adulthood show that identical twins are more alike than fraternal twins (even if reared apart) in:

personality traits such as extraversion (sociability) and neuroticism (emotional instability).

behaviors/outcomes such as the rate of divorce.

abilities such as overall Intelligence test scores.

ConcordanceThe probability that the second twin will have a certain trait if the first does. If the MZ concordance is higher than the DZ concordance that suggests genetic influence to the extent that the MZ twins were treated no more similarly than the DZ twins.

Identical Twins Raised ApartEven if raised apart, identical twins are still more similar to each other than to family they were raised by on:personality

abilities/IQ

attitudes

interests

specific fears

brain waves, heart rate

Adopted children also seem to be more similar to their genetic relatives than their environmental/nurture relatives

All of this means that it is worth investigating genetic influence on these behaviors.

Molecular genetics is an extension of behavior genetics that asks the question, “Which genes influence a particular behavior?”

Behavior Genetics

Molecular Genetics

Molecular Genetics

The Nucleus contains Chromosomes which in turn contain DNA (deoxyribonucleic acid)

Genes: Protein Makers

Genes: Protein makersSegments within DNA consist of genes that make proteins including enzymes and neurotransmitters.

Genes: Protein Makers

The Human Genome

46 chromosomes in 23 sets matched sets

X and Y chromosomes are not a matched set in males, who are missing some genes on the Y.

Each person’s chromosomes have the same gene locations as everyone else

Each biological parent donates half a set of chromosomes to his/her offspring.

This genetic protein assembly can be turned on and off by the environment, regulatory regions of the gene itself, or by other genes.

Almost any trait we see is a result of the complex interactions of many genes and countless other molecules.

How Genes Work

Smaller than genes: Nucleotides

Recall that a gene (and DNA generally) consist of sequences of nucleotide bases:

◦ A= adenine ◦ T = thymine ◦ G= guanine ◦ C =cytosine

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Smaller than Genes: Nucleotides

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SNPs Parent 1: A A C C T C TA C A CParent 2: A A C C T T TA C A C G

= Possible genotypes: CC, CT, TT

VNTRs

3 repeats: CCACTCAGG CCACTCAGG CCACTCAGG

2 repeats: CCACTCAGG CCACTCAGG

= Possible genotypes: 3R/3R, 3R/2R, 2R/2R

Variation in SNPs and VNTRs

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Vary dose of some treatment drug.

Associate any behavioral outcome with drug dose.

A common pattern is a drug dose-response.

Drug Dose-Response

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A single SNP can influence the rate or quality of the protein produced.

We can associate any behavioral outcome with genotype.

A common pattern is a gene dose-response.

Gene Dose-Response

We have found significant differences in RT by genotype on COMT at SNP #rs4680

Significant associations between a SNP or VNTR and a behavior commonly explain 3-12% of the variation in behavior.

Example ANOVA

We’ve also found significant differences in RT slope across trials by genotype on COMT at SNP #rs4680. Less than 25% of variance explained.

Example Slope (Multilevel Modeling)

Polygenic Inheritance – Process by which several genes interact to produce a certain trait; responsible for our most important traits.

Pleiotropic inheritance – the effect of a single gene on more than one characteristic

trait

traittraittrait

But Things Get Complicated

• Genes can influence traits, which influence responses, which influence the environment, which can influence gene activity.

• For example, a genetic predisposition influences a child to be restless and hyperactive evokes an angry response from his parents.

• Or, a stressful environment can trigger genes to manufacture neurotransmitters that lead to depression.

Gene-Environment Interaction

Interaction of Genes and Environment

Genes can turn each other on and off in response to environmental conditions

Epigenetics: the environment acts on the surface of genes to alter their activity

Example: shortened daylight triggers animals to hibernate

Example: obesity in adults can turn off weight regulation genes

Histones can be modified by enzymes. One of the most common modifications is methylation (adding a methyl group). This slows transcription (the copying of DNA into RNA so a protein can be built).

Longitudinal Study (vs Cross Sectional)

The SLC6A4 gene influences the level of serotonin, which is known to play a role in mood.

Example of Genetic Influence

There is a VNTR on the SLC6A4 gene.

Long version - a little over 50% of population

Short version - a little less than 50%

The researchers compared participants with a normal SLC6A4 (long) VNTR with participants with shorter alleles.

Specifically after stressful events.

Caspi et al. (2003)

Results

After stressful events, the participants with the shorter SLC6A4 VNTR were more likely to become depressed.

The SLC6A4 gene could be involved in vulnerability to depression.

Caspi et al. (2003)

Example Implications

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We can look at infant siblings of kids who have Autism

The infants don’t have autism, but they share 50% of their genes with their biological siblings

If the infants do poorly on some skill related to autism and then later go on to develop autism, we can identify which genes influence the development of autism

Identifying children earlier allows us to intervene and enroll infants in parent-infant programs that prevent the development of some symptoms and ameliorate the development of others

Identifying At-risk Children Earlier

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Some genes do not confer risk for problem behavior, but sensitivity to the environment

BDNF and MAOA are two of these

Children are more likely to grow up to be delinquent only if they have both a risk allele and they grow up in a harsh home environment

If we are kind to them, they grow up amazingly well – otherwise . . .

Knowing How to Change the Environment

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Treatment Refractory Depression and Treatment Resistant Obsessive –compulsive disorder

Finding a biological pathway is associated with particular, more severe symptoms may make these types of disorders easier to treat with medications

Finding Better Treatments for Intractable Psychiatric Disorders