Lecture 16: Brain Development and Population Genetics

Characteristics of genetic variants associated with common complex disorders

Allele frequency greater than 5%

Low effect size on protein function

Sensitive Window for ADHD

Pre-natal period (20 weeks) to perinatal period (1 year).

GWAS

Associates variant DNA alleles with having a disease or phenotype

EWAS

Associates the amount of methylation at individual CpG sites with having a disease or phenotype.

DNA methylation values

Generates value between 0 and1

• 0 = unmethylated

• 1 = completely methylated

• 0.5 = half of copies are methylated

CpG Methylation at a Gene’s Promoter

Suggests that the gene is inactive/not expressed.

CpG Methylation Across the Gene Body

Indicates that the gene is actively being transcribed.

Multiple Test Correction in GWAS/EWAS

Necessary due to the high number of false positives generated with a P-value of 0.05 on large data sets.
Set a lower P-value threshold → need. morecorrections

Importance of Tissue Type in EWAS

DNA methylation is cell-type specific; reflects gene activity in each cell type.

Examine methylation in tissue that bears phenotype of interest

Samples Used in EWAS for Diabetes

DNA samples from individuals with and without diabetes, likely from pancreatic tissue.

Frequent Cause of Monogenic Neurodevelopmental Disabilities

Mutated genes encode proteins related to epigenetic regulation, including chromatin or DNA methylation.

Effect of Cocaine Exposure on the Epigenome

Stimulates DA release, modifies gene expression through dopaminylation of histone 3, leading to lasting changes.

Preventing Dopaminylation via Genetic Mutation

Creating a missense mutation in histone 3 to replace glutamine 5 prevents dopamine attachment.