Genomics and Quantitative genetics

SL22019

What was the first whole organism to be sequenced

The bacteria Haemophilus influenzae (1995)

are changes in phenotype always due to changes in sequence?

not all changes in sequence causes changes in proteins

example is sickle cell anemia which is caused bu a single base pair point mutation in the b-globin gene

do synonymous mutation have no effect?

many studies suggest that non synonymous mutations can have no effect

can changes in a phenotype occur w out changes in sequence

• yes

• the position of a gene in a chromosome effect recombination and expression. potentially affecting its evolutionary rate

• recent work suggests that chromosomes also have a specific neighbourhood and changes in this pattern can affect phenotypes.

when was the hunome genome project launched and how much did it cost

1990

3 billion dollars

how many base pairs in human genome

3 billion

strategy for sequencing the human genome

• divide the task into smaller pieces: clone large pieces w known order and sequence them independently

• identify genetic markers as landmarks

• digest DNA into 300KB size

• clone fragments, identify and order clones necessary to reconstruct

• (when the human genome started there weren’t many genome markers)

genetic markers

• DNA sequencd w a known physical location on a chromosome

• location can be absolute, or relative to another marker

• when there is a variation on that sequence it is a useful landmark for an allele

• when the project started there was only 393 RFLP markers not sufficient to seq the human genome

celera and HGP

• graig venters

• 1998joined w HGP 

• 90% of human genome in 2001 

• 150,000 gaps

“complete” human seq

• 2003

• muhc improved and only 400 gaps

• reduced number of coding genes to 2400

• 92% of genome

main outcome of HGP

• the consortium model for tackling large projects

• a reference genome that allows the identification of genetic variation in humans

• technological changes have been truly revolutionary unleashing the power of genomics

finally complete human genome

• 2022

• gapless - telomere to telomere

• introduces nearly 200 million base pairs of seq containing 1956 gene predictions 99 are predicted to be protein coding

heritability and regression

• galton : resemblance of offspring and parents can be measured by regression

quantitative vs mendelian variation

• mendel described particulate inheritance (law of segregation and law of independent assortment)

• focuses on qualitative traits (classify henotypes into discrete classes)

• in modern genetics these are typically (genes of major effect, loss of function (KO) mutants)

molecular variation underlies trait variation

• genetically based trait variation reflects effects of DNA sequence variation (link genotype to phenotype by measuring up effects of loci to add up and predict)

• non genetic variation = the remainder

• but inherited trait variation can arise from epigenetic effects

R.A Fisher

-1928

reconciled mendelian inheritance w biometrics (continuous inheritance)

quantitative traits ar epolygenic - each affected by many genes of small effect

showed that all previous results in biometrics were compatible w mendelian inheritance

developed the infinitesmal model (can approx inheritance and evolution using a model w an infinte no of loci each w an infinitesmillay small effect

heritability and regression

fisher denomstrated that the slope of the regression line (offspring on mid parent) provides an estimate of the proportiion of variation that is additive genetic (heritable)

narrow sense heritability

can be conceptualised as the porportion of variation among parents will appear as variation among their offspring

continuous distributions

a trait affected by alleles at some arbitraty number of loci where

• each locus has 2 alleles w similar freqs and genotype freqs are in Hardy Weinberg proportions

• the alleles are codominant (additive)

a locus w an additive effect

codominance