Download Genome-wide Regulatory Complexity in Yeast Promoters

Genome-wide Regulatory
Complexity in Yeast Promoters
Zhu YANG
15th Mar, 2006
Reference
• C. S. Chin, J. H. Chuang, & H. Li. 2005.
Genome-wide regulatory complexity in
yeast promoters: Separation of
functionally conserved and neutral
sequence. Genome Research. 15(2):20513.
Outline
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Purposes
Methods
Results
Discussion
Purposes
• To separate functionally conserved and
neutral sequence.
• To know how much promoter sequence is
functional.
Methods
• Determine the local neutral mutation rates by
measuring the degree of sequence conservation
across the genome
• Determine what parts of yeast promoters evolve
neutrally
• Estimate the total amount of promoter sequence
under selection in promoters.
• Find out how much regulation acts on each gene
roughly by analyzing the length of sequence in
high conservation regions for each promoter.
Algorithms
• Calculation of substitution rates from
fourfold sites
• Mutational uniformity
• Separation of high and low conserved
regions with a hidden Markov model
• Genome-wide percentage of promoter
sites under selection
• z-score in Gene Ontology analysis
Neutral mutation rates are uniform
genome-wide
• Mutation rates are uncorrelated along the
yeast genome
• In contrast, mouse-human conservation
rates are significantly correlated along the
human genome at separations up to
several megabases
Autocorrelation in conservation
rates
Neutral mutation rates are uniform
genome-wide (Cont’d)
• There is a subset of genes was biased toward
high conservation by some secondary effect
• There are 92% of the genes mutate neutrally at
fourfold degenerate sites. The high conservation
values for the remaining 8% of the genes were
explainable by codon usage selection
• correlation of the normalized substitution rate
with codon adaptation index (CAI) was 0.67.
Distribution of normalized
conservation rates
Neutral conservation rates in
promoters
• Functional elements should be separated from
the neutral background, since conservation can
be due to shared ancestry.
• Hidden Markov model (HMM)
• Break the promoters into high conservation
regions (HCR) and low conservation regions
(LCR).
• the HCRs and LCRs gave a good approximation
to functional and neutral regions.
Separation of conserved blocks
from the background
Neutral conservation rates in
promoters (Cont’d)
• The HCRs, on the other hand, contained
an excess of functional elements.
• While the HCRs covered only 34.3% of the
promoter regions, they contained 71.6%
motifs in the promoters.
• The neutral rates in the LCRs were
consistent with the neutral rates obtained
from the fourfold site analysis
Distribution of the conservation rate
for promoter sequences
Genome-wide amount of promoter
sequence under selection
• Frequency of Conserved Blocks (FCB)
method was more robust than the HMM
for inferring the amount of selectively
conserved sequence
• Count the numbers of blocks of n
consecutive conserved bases in the
promoter sequences, which were then
compared to neutral expectations.
Requirements
• The frequency distribution of conserved
blocks in neutral sequence is known
• This neutral component can be extracted
from the real frequency distribution.
Distribution of the counts of blocks
of n consecutive conserved
bases
Estimate of the percentage of sites
evolving neutrally among various
species
Gene-specific selection in
promoters
• The HCRs provide a rough
characterization of the transcriptional
regulation in each promoter.
• most genes having 15%–25% of their
promoter sequence in HCRs.
• Protein sequence conservation was
correlated on a gene-by-gene basis with
HCR length
The Gene Ontology terms
• With the largest HCR length biases were those
involved in the energy generation and steroid
synthesis pathways, suggesting that these types
of genes have unusually complex regulation.
• The genes with the strongest protein sequence
conservation were not always those having the
longest HCR lengths, Catalysis, Basic
Biosynthesis, and Ribosomal Genes, for
example.
Nonsynonymous conservation
versus lengths of HCR
Discussion
• The neutral conservation rate is uniform across
yeast genomes. One nonselective possibility is
that yeast chromosomes are too short to have
heterogeneity in their mutational environment
• A significant fraction of promoter sequence was
under purifying selection.
• A typical function block may contain one or two
protein-binding sites; an upper bound of ∼10
transcription-factor-binding sites in a promoter.
• Genes involved in energy generation and steroid
synthesis may be subject to complex
transcriptional regulation.