Lecture 16: Brain Development and Population Genetics

What are two characteristics of genetic variants that are associated with common/complex/polygenic disorder?

Variant allele frequency is greater than 5% - common compared to other variant alleles

Low effect size of variant allele on protein function

What is thought to be the sensitive window for ADHD?

pre-natal period (20 weeks) to perinatal period (1 year)

A GWAS associates variant DNA alleles with having a disease or phenotype. What does an EWAS associate with having a disease or phenotype?

Amount of methylation at individual CpG sites scattered across the genome

DNA methylation value between 0 and 1.

0=unmethylated

1= completely methylated 0.5 = half of copies are methylated

An EWAS is designed to assess epigenetic marks that might affect gene expression. Does an EWAS assess the methylation on the DNA or on the histone protein tails\

Methylation directly on the DNA

CpG methylation at a gene’s promoter suggests what about its expresssion level? What about CpG methylation across the gene body?

At promoter - gene is inactive/not expressed

Gene body - gene is actively being transcribed

Why do you have to use a multiple test correction to determine the significance threshold for GWAS and EWAS studies?

P-value of 0.05 on large data sets generates many false positives

P-value is lower threshold → requires more corrections

Why is it preferable to examine methylation in DNA from tissue bearing the phenotype of interest in an EWAS?

DNA methylation is cell-type specific - different genes expressed in every cell

• CpG methylation reflects gene activity in each cell type

What samples would be used for an EWAS on diabetes, for example?

DNA samples from people with and without diabetes, tissue likely from the pancreas

What is a similarity underlying the cause of monogenic neurodevelopmental disabilities?

Mutated genes encode proteins that are related to epigenetic regulation - related to regulation or chromatin or DNA methylation

How does cocaine exposure change the epigenome?

Stimulates DA release in the ventral tegmental area (VTA) DA enters nucleus and binds to tails of H3 molecules, adds mark called H3Q5dop (dopaminylation) Alters gene expression at genes with dop mark - modification lasts for a while even without further exposure to cocaine

How could you prevent dopaminylation from happening by making a genetic mutant?

Genetic missense mutation in histone 3, replace glutamine 5 with a different amino acid

• Dopamine won’t be able to attach dop mark