BIOL335: Genetic selection

Measuring genetic selection

Paul Gardner

September 19, 2014

Paul Gardner Measuring genetic selection

Main questions

I Any questions from the last lecture?

I How can we measure selection?

I How much of the human genome is under selection?


One of the biggest surprises in the human genomesequence...

I The draft Human genome sequence was published in 2001I The haploid human genome contains approximately 20,000

protein-coding genesI Before that, the text-books predicted 100,000 protein-coding

genesI C. elegans has ≈ 20, 470 genes, Drosophila has ≈ 15, 682

genes, Baker’s yeast has ≈ 6, 607 genes and E. coli has≈ 5, 000 genes

I Just ≈ 2% of the human genome is protein coding


https://en.wikipedia.org/wiki/Human_genome

A conclusion from comparing the human and chimpgenomes

I “One of Clark and colleagues’ findings is that human enzymes foramino-acid breakdown (catabolism) have been under positiveselection. This is concordant with the generally high proportion ofmeat (and thus protein) in the human diet, at least in comparisonwith the more herbivorous chimpanzee and gorilla. The increasedcapacity to break down amino acids is not surprising in anotherrespect. For example, failure to catabolize phenylalanine has severaladverse effects, including brain damage. Overall, the finding lendssupport to theories that an increased proportion of meat in the dietof early humans was important for an increase in brain size.Regardless of that, there could also be ethical implications. If earlyhumans ate meat ’naturally’, then for example being vegetariancould be considered a personal choice rather than a universal ethicaldecision.”

Penny (2004) Evolutionary biology: Our relative genetics. Nature


How much is under “selection”...

I Genetic selection favours some genetic variation within apopulation over others.

I Negative selectionI Positive selection

I 3% to 8% of the human genome appears to be under negativeselection (8.2% according to Rands, et al. (2014))

Siepel et al. (2005) Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. GenomeResearch


https://en.wikipedia.org/wiki/Selection

https://en.wikipedia.org/wiki/Purifying_selection

https://en.wikipedia.org/wiki/Directional_selection

How can we measure “selection”?


Idea 1: compare rates of synonymous and non-synonymousmutations

I Compare the number of non-synonymous and synonymousmutations: dN

dS(also called the Ka

KSratio or ω)

# STOCKHOLM 1.0#33 unique RNA sequences, 1 peptide sequence#=GR PR1 G..A..D..V..T..H..P..P..A..G..D..#=GR PR3 GlyAlaAspValThrHisProProAlaGlyAspplatypus GGAGCAGACGTCACTCACCCCCCAGCCGGAGATopossum GGAGCAGATGTTACTCACCCTCCTGCTGGAGATsloth GGAGCAGACGTCACACACCCTCCCGCGGGGGATarmadillo GGAGCAGACGTCACGCACCCTCCGGCAGGGGATtenrec GGGGCCGACGTCACGCACCCCCCTGCGGGCGATelephant GGAGCGGATGTCACACACCCGCCTGCGGGGGATshrew GGCGCAGATGTCACGCATCCTCCAGCAGGGGAChedgehog GGAGCAGATGTCACACACCCCCCAGCAGGAGATmegabat GGAGCAGATGTCACACACCCTCCTGCAGGAGATmicrobat GGAGCAGATGTCACCCACCCCCCTGCAGGGGACdog GGAGCGGATGTCACACACCCCCCAGCCGGGGACcat GGAGCCGATGTCACGCACCCCCCAGCAGGGGAThorse GGAGCGGATGTCACACACCCTCCGGCAGGGGATpika GGAGCAGATGTCACTCACCCTCCAGCTGGGGATrabbit GGTGCAGATGTCACACACCCCCCAGCTGGAGATsquirrel GGAGCAGATGTCACTCACCCTCCAGCGGGAGATguinea_pig GGAGCAGATGTCACACACCCACCAGCGGGAGATmouse GGAGCAGATGTCACTCATCCGCCTGCTGGGGACrat GGAGCAGATGTCACTCATCCACCTGCTGGGGATkangaroo_rat GGAGCAGATGTTACACACCCTCCAGCAGGGGATtree_shrew GGCGCAGACGTCACGCACCCCCCGGCCGGGGAThuman GGAGCGGATGTCACACACCCCCCAGCAGGGGATtarsier GGTGCTGATGTCACACACCCCCCTGCAGGGGATmarmoset GGAGCAGATGTCACACACCCACCAGCAGGGGATzebrafinch GGAGCAGATGTCACTCACCCTCCCGCCGGGGATgreen_anole GGGGCAGACGTCACTCACCCGCCAGCCGGGGACxenopus GGAGCAGATGTTACACACCCACCTGCTGGTGATpufferfish GGTGCGGATGTTACTCATCCTCCTGCTGGTGATfugu GGGGCTGATGTTACTCACCCTCCAGCTGGTGATstickleback GGTGCAGACGTCACACATCCTCCAGCGGGTGATmedaka GGTGCCGATGTCACTCATCCTCCTGCCGGGGACzebrafish GGGGCAGATGTTACACACCCGCCGGCTGGTGATlamprey GGTGCCGATGTGACACACCCTCCAGCGGGAGAC//

https://en.wikipedia.org/wiki/Genetic_code


Interpreting dNdS

I dN & dS near zero is a bugger!

I log10(dN+δdS+δ )

I log10(dNdS + δ) & dS > 0

Histogram of log10(dN+δdS+δ)

log10((dN+δ)/(dS+δ))

Fre

quen

cy

−6 −4 −2 0 2 4 6

050

100

150

200

Histogram of log10(dN

dS+δ)

log10(dN/dS+δ)

Fre

quen

cy

−3 −2 −1 0 1 2

050

100

150

200


Problems with dNdS


Another idea, look for fast vs slow evolving regions



Finding extreme levels of conservation

I ELAVL4 (HuD) gene, an RNA-binding gene associated withparaneoplastic encephalomyelitis sensory neuropathy andhomologous to Drosophila genes with established roles inneurogenesis and sex determination


I See also: ultraconserved elements


Finding “accelerated evolution”

Pollard et al. (2006) An RNA gene expressed during cortical development evolved rapidly in humans. NatureHubisz & Pollard (2014) Exploring the genesis and functions of Human Accelerated Regions sheds light on theirrole in human evolution. Current Opinion in Genetics & Development


Idea 2: look at population variation

I Allele/SNP frequenciesI Alleles associated with harmful traits decrease in frequency

while those associated with beneficial traits become morecommon.

I Genome wide association studies (GWAS)I Selective sweepsI Tajima’s D (roughly, the difference between observed numbers

of SNPs and the expected)


Idea 3:

I Transposon-free regions

Simons et al. (2006) Transposon-free regions in mammalian genomes. Genome Res.


The End


Science

BIOL335: Genetic selection