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Analysis of sequence conservation at nucleotide resolution.

Asthana S, Roytberg M, Stamatoyannopoulos J, Sunyaev S - PLoS Comput. Biol. (2007)

Bottom Line: Our approach estimates the rate at which each nucleotide position is evolving, computes the probability of neutrality given this rate estimate, and summarizes the result in a Sequence CONservation Evaluation (SCONE) score.These regions are markedly enriched in individually conserved positions and short (<15 bp) conserved "chunks." Our results collectively suggest that the majority of functionally important noncoding conserved positions are highly fragmented and reside outside of canonically defined long conserved noncoding sequences.A small subset of these fragmented positions may be identified with high confidence.

View Article: PubMed Central - PubMed

Affiliation: Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.

ABSTRACT
One of the major goals of comparative genomics is to understand the evolutionary history of each nucleotide in the human genome sequence, and the degree to which it is under selective pressure. Ascertainment of selective constraint at nucleotide resolution is particularly important for predicting the functional significance of human genetic variation and for analyzing the sequence substructure of cis-regulatory sequences and other functional elements. Current methods for analysis of sequence conservation are focused on delineation of conserved regions comprising tens or even hundreds of consecutive nucleotides. We therefore developed a novel computational approach designed specifically for scoring evolutionary conservation at individual base-pair resolution. Our approach estimates the rate at which each nucleotide position is evolving, computes the probability of neutrality given this rate estimate, and summarizes the result in a Sequence CONservation Evaluation (SCONE) score. We computed SCONE scores in a continuous fashion across 1% of the human genome for which high-quality sequence information from up to 23 genomes are available. We show that SCONE scores are clearly correlated with the allele frequency of human polymorphisms in both coding and noncoding regions. We find that the majority of noncoding conserved nucleotides lie outside of longer conserved elements predicted by other conservation analyses, and are experiencing ongoing selection in modern humans as evident from the allele frequency spectrum of human polymorphism. We also applied SCONE to analyze the distribution of conserved nucleotides within functional regions. These regions are markedly enriched in individually conserved positions and short (<15 bp) conserved "chunks." Our results collectively suggest that the majority of functionally important noncoding conserved positions are highly fragmented and reside outside of canonically defined long conserved noncoding sequences. A small subset of these fragmented positions may be identified with high confidence.

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Conservation in Various Functional ClassesFor each functional class, the fraction of positions with SCONE p-value ≤ 0.005 is shown, both including (dark) and excluding (light) positions falling within MCS elements. Ancestral repeats are included as a control.
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pcbi-0030254-g003: Conservation in Various Functional ClassesFor each functional class, the fraction of positions with SCONE p-value ≤ 0.005 is shown, both including (dark) and excluding (light) positions falling within MCS elements. Ancestral repeats are included as a control.

Mentions: We therefore analyzed the distribution of SCONE p-values in all of the above types of functional elements, as well as CpG islands, a well-known sequence-based marker of functional elements. We found all categories of functional elements to exhibit statistically significant deviation from the uniform neutral distribution. The deviation of all classes of functional regions from the neutral distribution was explained almost entirely by a subset of positions with low SCONE p-values. The excess of conserved individual positions in functional regions compared to putatively neutral regions (ancestral repeats) is shown in Figure 3.


Analysis of sequence conservation at nucleotide resolution.

Asthana S, Roytberg M, Stamatoyannopoulos J, Sunyaev S - PLoS Comput. Biol. (2007)

Conservation in Various Functional ClassesFor each functional class, the fraction of positions with SCONE p-value ≤ 0.005 is shown, both including (dark) and excluding (light) positions falling within MCS elements. Ancestral repeats are included as a control.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2230682&req=5

pcbi-0030254-g003: Conservation in Various Functional ClassesFor each functional class, the fraction of positions with SCONE p-value ≤ 0.005 is shown, both including (dark) and excluding (light) positions falling within MCS elements. Ancestral repeats are included as a control.
Mentions: We therefore analyzed the distribution of SCONE p-values in all of the above types of functional elements, as well as CpG islands, a well-known sequence-based marker of functional elements. We found all categories of functional elements to exhibit statistically significant deviation from the uniform neutral distribution. The deviation of all classes of functional regions from the neutral distribution was explained almost entirely by a subset of positions with low SCONE p-values. The excess of conserved individual positions in functional regions compared to putatively neutral regions (ancestral repeats) is shown in Figure 3.

Bottom Line: Our approach estimates the rate at which each nucleotide position is evolving, computes the probability of neutrality given this rate estimate, and summarizes the result in a Sequence CONservation Evaluation (SCONE) score.These regions are markedly enriched in individually conserved positions and short (<15 bp) conserved "chunks." Our results collectively suggest that the majority of functionally important noncoding conserved positions are highly fragmented and reside outside of canonically defined long conserved noncoding sequences.A small subset of these fragmented positions may be identified with high confidence.

View Article: PubMed Central - PubMed

Affiliation: Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.

ABSTRACT
One of the major goals of comparative genomics is to understand the evolutionary history of each nucleotide in the human genome sequence, and the degree to which it is under selective pressure. Ascertainment of selective constraint at nucleotide resolution is particularly important for predicting the functional significance of human genetic variation and for analyzing the sequence substructure of cis-regulatory sequences and other functional elements. Current methods for analysis of sequence conservation are focused on delineation of conserved regions comprising tens or even hundreds of consecutive nucleotides. We therefore developed a novel computational approach designed specifically for scoring evolutionary conservation at individual base-pair resolution. Our approach estimates the rate at which each nucleotide position is evolving, computes the probability of neutrality given this rate estimate, and summarizes the result in a Sequence CONservation Evaluation (SCONE) score. We computed SCONE scores in a continuous fashion across 1% of the human genome for which high-quality sequence information from up to 23 genomes are available. We show that SCONE scores are clearly correlated with the allele frequency of human polymorphisms in both coding and noncoding regions. We find that the majority of noncoding conserved nucleotides lie outside of longer conserved elements predicted by other conservation analyses, and are experiencing ongoing selection in modern humans as evident from the allele frequency spectrum of human polymorphism. We also applied SCONE to analyze the distribution of conserved nucleotides within functional regions. These regions are markedly enriched in individually conserved positions and short (<15 bp) conserved "chunks." Our results collectively suggest that the majority of functionally important noncoding conserved positions are highly fragmented and reside outside of canonically defined long conserved noncoding sequences. A small subset of these fragmented positions may be identified with high confidence.

Show MeSH
Related in: MedlinePlus