Foundations of Genetic Research: A Primer How can something so tiny make such a big difference? Rebecca A. Lundwall Psychology 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

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

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

Fraternal and Identical Twins Twin & Adoption Studies Assess the impact of nature & nurture: study traits of siblings vs. identical twins see if siblings vary more than twins Fraternal “twins” from separate eggs are not any more genetically alike than other siblings. Identical twin: Same sex only Click to reveal sidebar. Fraternal twins are more alike than other siblings, however, in the home environment they share. They are raised at the same time in their parents’ lives, with the same number and age of siblings. Even identical twins, though, can have biological differences, if they have separate placentas (this happens in about one out of three times) and thus get different nourishment. Fraternal twin: Same or opposite sex

Identical vs. Fraternal Twins Study the traits of identical twins as they grow up together or separately (Minnesota Twin Family Study). Studies 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. Click to reveal sidebar. Instructor: In these and related studies, not only are identical twins more alike than fraternal twins, but fraternal twins are more alike than random strangers even though random strangers are also raised in different environments. Question for the students, in this slide and the next: which factor is being controlled here, and which factor is varying? [Answer: presumably, these studies are done on twins raised at first together, then having some adult time apart; if fraternal twins have more differences than identical twins, the only factor which has varied is the level of genetic similarity.]

Concordance The 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 Apart Even 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. Click to reveal bullets, then more in sidebar. Instructor: There are cases in which identical twins are separated at birth through adoption but are later found to be twins. The Minnesota Twin Family Study is the biggest example of this. Again, I suggest asking the students: which factor is being controlled here, and which factor is varying? Sidebar: Another critique is that the environments or “nurture” may be more similar for twins than for a pair of unrelated people because they look identical and thus are treated more similarly.

Molecular Genetics Behavior Genetics Molecular Genetics OBJECTIVE 9| Identify the potential promise and perils of molecular genetics. Molecular genetics is an extension of behavior genetics that asks the question, “Which genes influence a particular behavior?”

Genes: Protein Makers The Nucleus contains Chromosomes which in turn contain DNA (deoxyribonucleic acid) OBJECTIVE 3| Define chromosome, DNA, gene, and genome, and describe their relationships.

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

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. The genome: an organism’s entire collection of genes

How Genes Work 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. Click to reveal bullets. Note: there is rarely one single gene for one trait, and tiny differences in genes can influence big differences in appearance and behavior.

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 Meiosis: Each ova carries ½ of each chromosome with it’s sequence of nucleotides and the matching DNA strand (A pairs with T; C with G); likewise for each spermatozoon. When we say you inherited a C from your Dad and a T form you Mom we are only looking at ½ the strand on ½ a chromosome. Sequences are read in the way the human body reads them, via codons that make amino acids. Genes that code for proteins usually (but not always) begin with ATG - and end with TAA and CAA is not the same amino acid as AAC. Extra variability is added because homologous chromosomes (the halves) can be recombined so that tips of one homologous chromosome join with the chromosome of the other parent. This is called crossover and normally occurs when the homologous chromosomes break in the same places. This normal process is called genetic recombination. Nucleic acids are macromolecules.

Variation in SNPs and VNTRs Parent 1: AACCTCTACAC Parent 2: AACCTTTACACG = Possible genotypes: CC, CT, TT VNTRs 3 repeats: CCACTCAGG CCACTCAGG CCACTCAGG 2 repeats: CCACTCAGG CCACTCAGG = Possible genotypes: 3R/3R, 3R/2R, 2R/2R

Drug Dose-Response Vary dose of some treatment drug. Associate any behavioral outcome with drug dose. A common pattern is a drug dose-response. Most of you are familiar with the general design of drug studies. You give different doses of the drug to different groups, measure their performance on some outcome, and typically you see a dose versus response relationship that might look something like what you see on this slide.

Gene Dose-Response 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. SIMILAR, but we don’t assign people to groups. In the simplest case, one of these two alleles either increases or decreases how much protein is made, and in turn in how much neurotransmitter is available. If you get zero copies of that allele, then you’ll likely show better attention than someone who has one of two copies.. Instead of the amount of drug being the independent variable, we have genotype as proxy for the amount of protein, and in turn, the amount of neurotransmitter that is available. CLARIFY that we won’t always see this pattern.

Example ANOVA 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. NOT the same outcome measures (primary vs. derived); primary = direct RT without removing alerting effect of cues. This graph takes the average SD of 20 similar trials (10 right and 10 left target presentations) for each subject and groups by genotype. SD is not necessarily the outcome measure I will use (easily influenced by outliers) and will probably separate right and left targets at first, in case that makes a difference.

Example Slope (Multilevel Modeling) We’ve also found significant differences in RT slope across trials by genotype on COMT at SNP #rs4680. Less than 25% of variance explained. NOT the same outcome measures (primary vs. derived); primary = direct RT without removing alerting effect of cues. This graph takes the average SD of 20 similar trials (10 right and 10 left target presentations) for each subject and groups by genotype. SD is not necessarily the outcome measure I will use (easily influenced by outliers) and will probably separate right and left targets at first, in case that makes a difference.

But Things Get Complicated 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 trait

Gene-Environment Interaction 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. OBJECTIVE 8| Give and example of a genetically influenced trait that can evoke responses in others, and give another example of an environment that can trigger gene activity.

Interaction of Genes and Environment Example: shortened daylight triggers animals to hibernate 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: obesity in adults can turn off weight regulation genes Click to reveal bullets and examples. The main mechanism for epigenetic change is the methyl molecule on DNA which essential deactivates it, keeping the gene from coding proteins. Sample of some of the citations on the obesity result at the bottom: http://www.nature.com/ijo/journal/v32/n7s/full/ijo2008240a.html http://www.bcm.edu/news/item.cfm?newsID=1166 Some traits, such as the overall design of our bodies, are set by genes. Other traits, such as physical and mental abilities, develop in response to experience. Genetic traits influence the social environment, which in turn affects behavior.

Histones can be modified by enzymes 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).

Example of Genetic Influence Longitudinal Study (vs Cross Sectional) The SLC6A4 gene influences the level of serotonin, which is known to play a role in mood.

Caspi et al. (2003) 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.

Example Implications

Identifying At-risk Children Earlier 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 improved diagnosis and treatment identifying genetic cause also helps with teasing apart genetic from environmental causes -- so can help identify non-genetic targets provide targets for medical treatments

Knowing How to Change the Environment 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 . . .

Finding Better Treatments for Intractable Psychiatric Disorders 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