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Researchers Find Role for Chromatin in Genetic Variation

NEW YORK (GenomeWeb News) – Chromatin structure can influence genetic variation and, consequently, help shape genomes over time, according to research scheduled to appear online today in Science Express.
A group of researchers from Japan and the US mapped the position of nucleosome cores, substitutions, and indels onto the genome of medaka, or Japanese killifish (Oryzias latipes). The team found that the incidence of genetic variation oscillated in the genome — and the patterns of these oscillations reflected nucleosome position. Insertions and deletions were more common where nucleosome occupancy was minimal, whereas point mutations peaked along with maximal nucleosome occupancy.
“These data exemplify the potential for genetic activity (transcription) and chromatin structure to contribute in molding the DNA sequence on an evolutionary time scale,” lead author Shin Sasaki and colleagues wrote.
Chromatin, a condensed structure containing proteins and nucleic acids, is made up of smaller units called nucleosomes consisting of roughly 150 base pairs of DNA wrapped around histones. Previous research has implicated these structures in everything from transcription and gene expression to DNA repair.
In an effort to determine whether chromatin structure influences DNA sequence variation, a research group led by Stanford University pathology and genetics researcher Andrew Fire and University of Tokyo computational biologist Shinichi Morishita compared the patterns of nucleosome occupancy and genetic variation in the killifish genome.
To pinpoint regions of genetic variation in the genome, the researchers first compared the genome sequences of two inbred Japanese killifish strains called Hd-rR and HNI. The strains are closely related and can interbreed, but their genomes differ at about 3.4 percent of their nucleotides. 
Next, the group used Illumina sequencing to generate roughly 38.5 million 5’ mRNA tags generated from Hd-rR killifish embryos between one day and two weeks old. About 68 percent of the tags aligned to the killifish genome and the team applied a clustering algorithm to find active transcription start sites.
From there, they calculated the substitution and indel rates within a thousand base pairs of transcription start sites. These variations rarely occurred at transcription start sites themselves. But the frequency of substitutions and insertions and deletions oscillated periodically on either side of the transcription start sites.
The substitution rate formed periodic peaks and valleys every 200 base pairs or so — peaking about 100 and 300 base pairs from transcription start sites. Insertions and deletions larger than one base pair also oscillated over about 200 base pairs. But the frequency of these indels peaked 200, 400, and 600 base pairs from transcription start sites — a pattern opposite to that observed for substitutions.
Because they suspected that nucleosomes contributed to these patterns, the researchers decided to overlay information about nucleosome position onto their map of genetic variation in the medaka genome.
To do this, the researchers sequenced 67 million reads from the mono-nucleosome core DNAs of killifish blastulae, half day old embryos that still had some characteristics of germline cells. Nearly 56 percent of these tags mapped onto the killifish genome.
They reported that nucleosomes mapped about every 200 base pairs downstream of transcription start sites, with minimal occupancy 200, 400, and 600 base pairs away of the transcription start sites. That suggests that insertions and deletions larger than a single base pair are occurring most often in DNA linker regions between nucleosomes, whereas substitutions tend to occur coincident with peak nucleosome occupancy.
The researchers speculated that transcription-coupled DNA repair or sequence composition could contribute to the nucleosome sequence effects. While they noted that transcription-coupled DNA repair seems to contribute to the natural sequence variation in some regions of the genome, the researchers suggested that chromatin structure itself influences the observed mutational periodicity.
“[T]he biases in genetic variation seem most likely to represent structural constraints of the chromatin template during the mutagenic processes that Medaka has encountered during evolutionary time,” they wrote.
And, the authors noted, it is possible that such interplay between chromatin structure and sequence mutagenesis and repair may have shaped the genomes of other organisms during evolution as well.
“Our working model for the basis of structural variation between the genomes of these two inbred medaka strains is that chromatin structure influences mutagenesis, which in turn influences genetic variation,” the researchers concluded. “We expect the influence of chromatin structure to be a general feature of sequence evolution throughout the genome and the biosphere.”

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