IB 360 Wk 5 Complex Traits and GWAS & Wk6 Inbreeding and Pedigrees

Sickle-cell Disease (SCD)

• interferes with ability of red blood cells to carry oxygen

• impede blood flow

What are some health complications of SCD?

-chronic pain

-stroke

-lung problems

-infections

-kidney disease

Discrete Trait

-traits with distinct separate categories, no intermediates

Monogenic Obesity 

• rare, early-onset, severe

• mutation in a single gene that affects control of appetite/ metabolism, single-gene defects 

Polygenic Obesity 

-hundreds of polymorphisms that each have a small effect 

-also affected by environment 

Quantitative/ Continuous Trait Definition and Example

• exhibit a range of phenotypes 

• BMI

• Usually continuous Distribution

Threshold Characteristic 

-trait controlled by many genes, but expressed in an all or none way

-trait only appears once a certain threshold is reached 

What type of traits often contribute to complex traits? 

-quantitative (continuous) traits 

What are the 4 components of phenotypic variance?

1) Genotype Variation

2) Environmental Variation

3) Genotype-Environment Interaction 

4) Developmental Error 

Heritability

-how much of the difference in traits between individuals are due to genetic differences rather than environment 

High vs Low Heritability 

-high heritability means most variation comes from genes 

-low heritability means most variation comes from environment or other factors 

Complex Traits 

-traits influenced by many genes and environmental factors than by a single gene

Tools to find genes that contribute to complex traits within a species

1) Quantitative Trait Loci Mapping (need to make breeding group, not good for studying in humans)

2) Genome-Wide Association Studies (GWAS)

Tools to find genes that contribute to complex traits between species

phylogenomic- combines phylogenetics and genomics to understand how species are related and how genes evolve

GWAS Process

-uses sequencing tech to identify regions in genome that may affect the trait of interest 

-looks for correlations between trait and known genetic mutations 

Does GWAS identify the alleles and genes linked to a trait?

-No, GWAS identifies loci associated with a trait, but each region has many genes

Haplotype

Group of SNPs located close together on a chromosome

4 General Steps in GWAS

1) Identify the disease/trait of interest and select appropriate study population 

2) Genotype for SNPs to get haplotypes 

3) Association Tests 

4) Look at regions near the haplotypes with high association 

Why are novel regions in GWAS closer to the dashed line and not the tall peaks? 

• novel regions are newly discovered, may have smaller effects or fewer supporting samples

Where regions of DNA do most GWAS hits fall in?

non-protein coding regions

What 3 types of alleles are GWAS best for?

1) Rare alleles with highly penetrant mutations

2) Intermediate frequency alleles with moderate effects

3) Common frequency alleles with small effects

What is Missing heritability in GWAS?

-part pf the trait genetic influence we know exists, but GWAS hasn’t been able to find yet 

Infinitesimal Model

-variation in quantitative traits is influences by a very large number of genes that make very small contribution to phenotype

Polygenic Risk Scores (PRS)

-Adding up effects of genetic variants across the genome to get genetic risk for a trait/disease

What are limitations of PRS?

-not as good as using family history

-relative risk, not absolute