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A H igh- R esolution M ap of H uman E volutionary C onstraint U sing 29 M ammals. Kerstin Lindblad-Toh, et al. 2011 Jimmy Ao Gordon Man. Intro. ~1.5% of the human genome encodes sequences

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a h igh r esolution m ap of h uman e volutionary c onstraint u sing 29 m ammals

A High-Resolution Map of Human Evolutionary Constraint Using 29 Mammals

Kerstin Lindblad-Toh, et al. 2011

Jimmy Ao

Gordon Man

intro
Intro
  • ~1.5% of the human genome encodes sequences
  • Previous comparative analysis with mouse, rat, and dog genomes show that at least 5% is under purifying selection
    • Removing alleles that are deleterious
  • Previous studies could estimate percentage of genome under constraint
    • Had difficulty finding the constrained elements
intro1
Intro
  • Sequence mammalian genomes to identify functional elements in human genome
  • Used 29 Eutherian (placental) genomes
    • Achieve maximum divergence across four major mammalian clades
  • Identified 4.2% of the human genome as constrained
    • 60% of these bases have potential function
slide4

Figure 1. A phylogenetic tree of all 29 mammals used in this analysis based on the substitution rates in the MultiZ alignments.

Species

blue - finished genomes

green - high quality drafts

black - 2x assemblies

branches

red≥10 substitutions/100bp

blue <10 substitutions/100bp

detection of c onstrained s equences
Detection of Constrained Sequences
  • Compared genome-wide conservation of ancestral repeats using multiple statistical test
    • SiPhy-ω statistic measures substitution rates
    • SiPhy-π like ω but in addition measures biased substitution patterns
    • PhastCons statistics
  • All statistical test showed similar results
  • estimated that 5.36% of genomes are under evolutionary constraint
    • Emsembl and PAML
  • detected an additional 1.3% of the human genome in constraint elements from SiPhy-π
slide6

Figure S7.

Biased nucleotide substitution patterns identifies positions where two bases appear equally constraint and correlating with SNPs in the human population.

constraint within the human population
Constraint within the human population
  • Mammalian constraint elements correlated to human constraint elements
  • Mammalian constrained elements had lower Small Nucleotide Polymorphisms (SNPs)
    • more contained elements had even lower SNPs
  • Biases substitution patterns in mammal SNPs were similar to ones observed in humans
    • same allele preference in both mammalian and human evolution
rna s tructures and f amilies of s tructural e lements
RNA Structures and Families of Structural Elements
  • Used evolutionary signatures characteristic of conserved RNA secondary structures to reveal 37,381 candidate structural elements
    • Found using EvoFold and RNAz 2.0
conservation p atterns in promoters
Conservation Patterns in Promoters
  • Categorized promoters into three categories
    • High constraint promoters
      • ~66% high constraint promoters associated with CpG islands
      • Involved with development
    • Low constraint
      • ~41% associated with CpG islands
      • Immunity, reproduction and perception
    • Intermittent constraint
      • Basic cellular functions
      • ~66% intermittent constraint promoters associated with CpG islands
identifying motifs
Identifying Motifs
  • More genomes did not help discover new motifs
    • Rat, mouse, and dog genomes found majority of motifs
  • Better in detecting individual motifs and predicting their target sites
  • Created network linking 375 motifs to predicted targets
    • Median of 21 predicted regulators per target gene
  • Compared results to chromatin immunoprecipitation (ChIP) experiments
    • Determines whether specific proteins are associated with specific genomic regions
    • Strong agreement between motif-based targets and ChIP
codon specific selection
Codon Specific Selection
  • Ratio dN/dS of non-synonymous to synonymous codon substitutions as evidence of positive selection (>1) or negative selection (<1)
  • Positive selection genes involved in immune response and taste perception
    • Unexpected functions such as meiotic chromosome segregation and DNA-dependent regulation of transcription
  • Localized positive selection was enriched in core biochemical processes, including microtubule-based movement, DNA topological change and telomere maintenance
mobile elements
Mobile Elements
  • DNA that can move around the genome
    • When retained and trait function changes = exaptation (ex. feathers)
  • Found over 280,000 mobile element exaptations common to mammalian genomes
    • Compare to 10,000 previously recognized cases
  • Often only a small fraction (median ~11%) of each mobile element is constrained
  • Recent exaptations are generally found near ancestral regulatory elements
applications
Applications
  • Genome 10k effort
    • Genomic database of 10,000 vertebrates
  • New model organisms
  • Molecular evolutionary genetics
  • Encyclopedia of DNA elements
    • international effort to build a database of functional elements in the human genome
  • NIH Roadmap Epigenomics Project
    • human epigenomic data
  • Human biology, health, and disease
    • Overlap with known disease elements
summary
Summary
  • Using a wide array of bioinformatics they compared 29 mammalian genomes.
  • 5.5% of the human genome has undergone purifying selection
    • Decrease frequency in alleles
    • Found constrained elements make up 4.2% of the genome
      • Suggest possible functions to 60% of constrained bases
        • New coding exons, stop codons, >10,000 regions of overlapping synonymous constraint within protein-coding exons
  • 220 candidate RNA structural families
    • million elements overlapping potential promoter, enhancer and insulator regions
  • >280,000 mobile elements
  • 1,000 human and primate accelerated elements
    • Highly conserved species specific regions