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Hundreds of conserved non-coding genomic regions are independently lost in mammals.

Hiller M, Schaar BT, Bejerano G - Nucleic Acids Res. (2012)

Bottom Line: However, CNE losses that do occur can be associated with phenotypic changes, exemplified by pelvic spine loss in sticklebacks.Our study uncovers an interesting aspect of the evolution of functional DNA in mammalian genomes.Experiments are necessary to test if these independently lost CNEs are associated with parallel phenotype changes in mammals.

View Article: PubMed Central - PubMed

Affiliation: Department of Developmental Biology, Stanford University, Stanford, California 94305, USA. hiller@mpi-cbg.de

ABSTRACT
Conserved non-protein-coding DNA elements (CNEs) often encode cis-regulatory elements and are rarely lost during evolution. However, CNE losses that do occur can be associated with phenotypic changes, exemplified by pelvic spine loss in sticklebacks. Using a computational strategy to detect complete loss of CNEs in mammalian genomes while strictly controlling for artifacts, we find >600 CNEs that are independently lost in at least two mammalian lineages, including a spinal cord enhancer near GDF11. We observed several genomic regions where multiple independent CNE loss events happened; the most extreme is the DIAPH2 locus. We show that CNE losses often involve deletions and that CNE loss frequencies are non-uniform. Similar to less pleiotropic enhancers, we find that independently lost CNEs are shorter, slightly less constrained and evolutionarily younger than CNEs without detected losses. This suggests that independently lost CNEs are less pleiotropic and that pleiotropic constraints contribute to non-uniform CNE loss frequencies. We also detected 35 CNEs that are independently lost in the human lineage and in other mammals. Our study uncovers an interesting aspect of the evolution of functional DNA in mammalian genomes. Experiments are necessary to test if these independently lost CNEs are associated with parallel phenotype changes in mammals.

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CNE losses in seven mammals. (A) For each CNE loss, we inferred the branch in the phylogenetic tree along which the loss likely happened by parsimony. The total number of observed losses is shown above each branch. Losses in branches leading to internal tree nodes have a loss or missing data for all descendant species. On the right, we show assembly coverage and available Sanger sequencing reads for the species where we search for CNE losses. (B) The vast majority of shorter assembly regions that comprise a CNE loss (region between the upstream/downstream aligning blocks is <500 bp) can be validated by unassembled sequencing reads that span the assembly region of CNE-loss species. (C) The frequency of CNE losses is strongly correlated with the branch length (neutral substitutions per site) from the eutherian (placental mammal) ancestor. (D) Plotting the distance between the aligning blocks in the reference (human genome, y-axis) and the CNE-loss (x-axis) genome shows that many CNE losses involve a large deletion. This trend is strongest in the species with the shortest branch length (horse, elephant). Linear regression line is in red.
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gks905-F1: CNE losses in seven mammals. (A) For each CNE loss, we inferred the branch in the phylogenetic tree along which the loss likely happened by parsimony. The total number of observed losses is shown above each branch. Losses in branches leading to internal tree nodes have a loss or missing data for all descendant species. On the right, we show assembly coverage and available Sanger sequencing reads for the species where we search for CNE losses. (B) The vast majority of shorter assembly regions that comprise a CNE loss (region between the upstream/downstream aligning blocks is <500 bp) can be validated by unassembled sequencing reads that span the assembly region of CNE-loss species. (C) The frequency of CNE losses is strongly correlated with the branch length (neutral substitutions per site) from the eutherian (placental mammal) ancestor. (D) Plotting the distance between the aligning blocks in the reference (human genome, y-axis) and the CNE-loss (x-axis) genome shows that many CNE losses involve a large deletion. This trend is strongest in the species with the shortest branch length (horse, elephant). Linear regression line is in red.

Mentions: We further discarded losses that have sequence similarity to any locus in the genome or to any of the unassembled sequencing reads (traces) of the respective species using lastz (24). This additional filter step excludes false losses that are due to genome assembly errors, errors in the multiple alignment and CNE translocations to a different locus. It should be noted that all of the species where we search for CNE losses have at least 25 GB of trace data (Figure 1A, Supplementary Table S7).Figure 1.


Hundreds of conserved non-coding genomic regions are independently lost in mammals.

Hiller M, Schaar BT, Bejerano G - Nucleic Acids Res. (2012)

CNE losses in seven mammals. (A) For each CNE loss, we inferred the branch in the phylogenetic tree along which the loss likely happened by parsimony. The total number of observed losses is shown above each branch. Losses in branches leading to internal tree nodes have a loss or missing data for all descendant species. On the right, we show assembly coverage and available Sanger sequencing reads for the species where we search for CNE losses. (B) The vast majority of shorter assembly regions that comprise a CNE loss (region between the upstream/downstream aligning blocks is <500 bp) can be validated by unassembled sequencing reads that span the assembly region of CNE-loss species. (C) The frequency of CNE losses is strongly correlated with the branch length (neutral substitutions per site) from the eutherian (placental mammal) ancestor. (D) Plotting the distance between the aligning blocks in the reference (human genome, y-axis) and the CNE-loss (x-axis) genome shows that many CNE losses involve a large deletion. This trend is strongest in the species with the shortest branch length (horse, elephant). Linear regression line is in red.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3526296&req=5

gks905-F1: CNE losses in seven mammals. (A) For each CNE loss, we inferred the branch in the phylogenetic tree along which the loss likely happened by parsimony. The total number of observed losses is shown above each branch. Losses in branches leading to internal tree nodes have a loss or missing data for all descendant species. On the right, we show assembly coverage and available Sanger sequencing reads for the species where we search for CNE losses. (B) The vast majority of shorter assembly regions that comprise a CNE loss (region between the upstream/downstream aligning blocks is <500 bp) can be validated by unassembled sequencing reads that span the assembly region of CNE-loss species. (C) The frequency of CNE losses is strongly correlated with the branch length (neutral substitutions per site) from the eutherian (placental mammal) ancestor. (D) Plotting the distance between the aligning blocks in the reference (human genome, y-axis) and the CNE-loss (x-axis) genome shows that many CNE losses involve a large deletion. This trend is strongest in the species with the shortest branch length (horse, elephant). Linear regression line is in red.
Mentions: We further discarded losses that have sequence similarity to any locus in the genome or to any of the unassembled sequencing reads (traces) of the respective species using lastz (24). This additional filter step excludes false losses that are due to genome assembly errors, errors in the multiple alignment and CNE translocations to a different locus. It should be noted that all of the species where we search for CNE losses have at least 25 GB of trace data (Figure 1A, Supplementary Table S7).Figure 1.

Bottom Line: However, CNE losses that do occur can be associated with phenotypic changes, exemplified by pelvic spine loss in sticklebacks.Our study uncovers an interesting aspect of the evolution of functional DNA in mammalian genomes.Experiments are necessary to test if these independently lost CNEs are associated with parallel phenotype changes in mammals.

View Article: PubMed Central - PubMed

Affiliation: Department of Developmental Biology, Stanford University, Stanford, California 94305, USA. hiller@mpi-cbg.de

ABSTRACT
Conserved non-protein-coding DNA elements (CNEs) often encode cis-regulatory elements and are rarely lost during evolution. However, CNE losses that do occur can be associated with phenotypic changes, exemplified by pelvic spine loss in sticklebacks. Using a computational strategy to detect complete loss of CNEs in mammalian genomes while strictly controlling for artifacts, we find >600 CNEs that are independently lost in at least two mammalian lineages, including a spinal cord enhancer near GDF11. We observed several genomic regions where multiple independent CNE loss events happened; the most extreme is the DIAPH2 locus. We show that CNE losses often involve deletions and that CNE loss frequencies are non-uniform. Similar to less pleiotropic enhancers, we find that independently lost CNEs are shorter, slightly less constrained and evolutionarily younger than CNEs without detected losses. This suggests that independently lost CNEs are less pleiotropic and that pleiotropic constraints contribute to non-uniform CNE loss frequencies. We also detected 35 CNEs that are independently lost in the human lineage and in other mammals. Our study uncovers an interesting aspect of the evolution of functional DNA in mammalian genomes. Experiments are necessary to test if these independently lost CNEs are associated with parallel phenotype changes in mammals.

Show MeSH
Related in: MedlinePlus