GN 301 Module 7: Heritability, GWAS, and QTL

Twins

  • Monozygotic: MZ- one egg splits and produces two individuals (identical twins)
  • Dizygotic: DZ- two eggs produce two individual (fraternal twins)
  • Super Twins: having a combination of identical and fraternal twins in one pregnant

When do most identical twins separate? How does time of the splitting of the embryo affect whether or not there are 2 placentas (chorions)?

  • Almost 2/3 split is after day 5 and before day 9 so they share the chorion but have separate amnions. The chorion develops into the placenta, and placentas can be counted when they are delivered at birth.
  • About 1/3 separate prior to day 5 resulting in separate chorions and separate amnions
  • About 1% have single amnion and chorion since embryo splits after these tissues split. This can be a bit risky since the twins are housed in the same amniotic sac
Inheritance of Twinning
  • There is no evidence that monozygotic twinning is inherited. The frequency across a variety of populations, ethnicities and countries is about 3/1000 pregnancies.
  • However there is evidence that fraternal twinning is inherited. There are differences in fraternal twin rates in different geographical regions and among different racial groups. The frequency also increases with an increase in maternal age.

Quantitative Traits often assumed to be distributed in a normal distribution

Phenotype = Genotype + Environment

Heritability

  • Define Heritability: the proportion of phenotypic variance that is due to genetic effects
  • Define Vp: variance seen in phenotype
  • Define VG: variance due to genetic effects
  • Define VE: variance due to environmental effects
  • VP = VG + VE
  • Compare MZ raised together and DZ raised together to estimate genetic effects

Concordance:

  • Define Concordant: if twins same for a trait
  • Define Discordant: if twins differ for a trait
  • Concordance using twin studies- describe
    • If the MZ and DZ values are similar, most of the variation in phenotype is due to variance in environmental effects which indicates a low heritability.
    • If there is a low MZ value but it is still quite higher than the DZ value, there is a genetic predisposition, but a low to moderate heritability for the trait.
    • High MZ: Low DZ indicates significant role of the variance of genetic effects in the phenotypic variance
    • Similar MZ and DZ indicates a lot of variation is due to variance in environmental effects
    • Low MZ but still much higher than DZ indicates genetic predisposition, but variance due to environmental factors is important in the variance of the phenotypes for this trait

Concordance Eg. MZ:DZ ratios are given for 4 traits. According to these data, which trait has the highest heritability?

  1. Trait A: 84:14
  2. Trait B: 95:82
  3. Trait C: 51:25
  4. Trait D: 81:65
  • Highest heritability is where high MZ: low DZ. So 1) ==Trait A has highest heritability.==

Heritability DOES NOT say how much genes affect the trait. It DOES say how much genes affect the variation in the trait. \n

QTLs and GWAS

  • QTL stands for Quantitative Trait Loci
  • Examples of commonly used markers are SNP and microsatellite regions
    • The idea is to correlate the presence of a specific molecular marker with the presence of a phenotype and the absence of the marker with the absence of the phenotype.
    • SNPs are single nucleotide polymorphisms which are single base pair changes that occur in at least 1% of the population.
    • Microsatellite regions are short sequences repeated in tandem (STRs).
  • GWAS stands for Genome Wide Association Studies
    • Purpose of GWAS
    • It allows us to identify genes that are associated with quantitative traits.
  • In GWAS studies, a trait is associated with gene markers in a biological population (typically a random mating population) as opposed to looking at progeny from controlled crosses

Researchers use molecular genetics techniques to scan entire genome for regions that show statistical importance for a trait. This allows researchers to identify genes that are associated with quantitative traits.

  • Techniques used in GWAS
    • Gene Chip (Microarray) shows the presence and absence of specific SNP patterns. Single stranded SNP DNA sequences (probes) are on the chip. The chip is incubated with an individual’s DNA and the sequences that are present bind to the probes. A computer then determines which SNPs are present. The information can be combined with that of many people to identify genes whose presence is correlated with the presence of a phenotype or disorder and whose absence is correlated with the absence of a disorder. These sequences can be located to chromosomes and candidate genes can be identified based on proximity to the correlated sequences.
  • Candidate genes identified in GWAS experiments must be validated!
    • Once a candidate gene is identified as being correlated with a trait, further research has to occur to validate the importance of the gene for that trait. Further study on gene regulation and possible targets for therapy can then be done.