W1L2 Thu genetic contribution to human traits

Question 1

What is Type 2 diabetes

Answer 1

• Pancreatic dysfunction, mid-life onset
• Impacts many organ systems
• Both environmental and genetic components
• “Lifestyle disease” but predisposition runs in families
• Sizeable genetic component
• On average, 10-year decrease in life expectancy
• 2015: 392 million people diagnosed globally
• 2018: 1 in 7 dollars spent in healthcare in USA is to treat diabetes (or its complications)
  -50% of diabetes risk is genetic

Question 2

Why does gene expression vary

Answer 2

• Evolutionary answer: it makes sense for gene expression to vary because variation makes a population more capable of surviving novel environments
• Mechanistic answer: it varies because of biological systems
• DNA:
• due to DNA sequence of that gene, around that gene and sequence elsewhere in the genome?
• Environment:
• Cellular environment?
• Tissue microenvironment?
• Lifestyle choices?
• Other genes?
• (is that gene or is that environment?)

Question 3

What is QTLs and eQTLs.

Answer 3

• To examine the genetic causes of variation in gene expression levels, we can search for eQTLs
• A QTL is a genetic region (locus) associated with a particular quantitative phenotype
• eQTL: expression quantitative trait locus

Question 4

What do we need to know to predict risk

Answer 4

-How many loci
-Which loci
-How do they contribute
-where in the genome are these loci (least important)

Question 5

EQTL discovery and math

Answer 5

• To identify eQTLs, test each SNP near a gene for an association between genotype and expression levels of the gene:
  𝐸𝑥𝑝𝑟𝑒𝑠𝑠𝑖𝑜𝑛 ~ 𝐺𝑒𝑛𝑜𝑡𝑦𝑝𝑒 𝑎𝑡 𝑆𝑁𝑃 + 𝑒𝑟𝑟𝑜𝑟 𝑡𝑒𝑟𝑚
• If genotype is significantly associated with expression, that SNP is an eQTL for that gene

Question 6

EQTL acting in cis and trans

Answer 6

• An eQTL impacts the expression of a focal gene in a cis manner…
• But these cis effects can impact downstream genes in a trans manner
• A cis eQTL tends to impact expression levels more than a trans eQTL.
• (But there are many more possible trans eQTLs than cis eQTLs for a given gene.)
  -few cis= many trans eQTL

Question 7

What is genetic architecture

Answer 7

the underlying genetic basis of a phenotypic trait and its variational properties

Question 8

Genes as a network

Answer 8

• Core genes impact traits directly.
• Peripheral genes can only affect traits indirectly
• Perturbing a gene impact the rest of the network -(nearly) all genes have cis eQTLs.
• Thus, a cis eQTL for a peripheral gene will impact a core gene in a trans fashion.

Question 9

The omnigenic model of human traits

Answer 9

• Asserts that most genes affect most traits, but they do not do so equally.
• A single gene is core for some traits and peripheral for other traits
• Perturbations at different points in the network lead to different phenotypic outcomes…and to different diseases.

Question 10

Core idea of the Omnigenic model

Answer 10

1. Complex traits are the product of core and peripheral gene network
2. Any given peripheral gene will contribute little, compared to a given core gene…
   * But there’s many of them!
   * So as a whole, peripheral genes contribute a lot!
3. Since all genes are connected, most genes contribute to most traits