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BGI's Silkworm Study Highlights Potential of Large-Scale Resequencing for Population Research

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By Andrea Anderson

A recent study led by researchers at the Beijing Genomics Institute is highlighting the value of resequencing many individuals from distinct populations of the same or closely related species.

The team reported online in Science last week that it has resequenced the genomes of silkworms from 11 wild and 29 domestic lines. By comparing the sequences with one another, they found genetic differences that apparently coincide with the transition from wild to domestic silkworms over some 5,000 years, providing clues about commercially valuable traits.

"Currently, we are also performing other similar resequencing projects," Jun Wang, deputy director of BGI-Shenzhen, told In Sequence by e-mail. "The method we developed and used in silkworm can also apply to other organisms, and it was a new milepost in population genome analyses."

The researchers used the Illumina Genome Analyzer II to sequence 40 silkworm genomes to about three-fold coverage each. They then analyzed the genomic data, looking for SNPs, insertions and deletions, and structural variants. Compared with the silkworm reference, the team found almost 16 million SNPs, more than 300,000 small indels, and more than 35,000 structural variants in the resequenced genomes.

"We systematically identified the genetic variants among these varieties," Wang told In Sequence's sister publication GenomeWeb Daily News. "Our strategy here provides a nearly complete genome-level variation map, which gives more reliable information on genetic polymorphisms in a population."

Although they generated sequence data from both unpaired and paired-end libraries, the researchers noted that paired-end data was generally more informative, providing a higher percentage of unique alignments. Even so, Wang said, there is still a place for the single-end reads, particularly for applications such as miRNA, digital gene expression, and exome sequencing studies.

Once the team had sequence data for both wild and domestic silkworms, it was able to look for domestication-related genetic patterns.

The domestic silkworm, Bombyx mori, typically has larger cocoons and produces more silk than its wild counterpart, B. mandarina. B. mori is also dependent on humans for protection and even mate selection, co-author Rasmus Nielsen, a researcher affiliated with the University of Copenhagen and the University of California at Berkeley, told In Sequence.

"[T]o convert B. mandarina into B. mori, it also must have been necessary to select insects that could tolerate human proximity and handling as well as extensive crowding, while being relatively docile and non-escapist," Wang explained. "At the same time, domesticated silkworms may have lost some [characteristics] that enabled them to avoid predators, fend off disease, and tolerate large temperature changes or variations in food supply, which were no longer needed in the protected environment of a rearing house."

In the past, researchers have used information about silkworm geography and generation time to try to understand domestication. But the process is still poorly understood.

"I think what's exciting about this project is that we have a domesticated and wild variety of the same organism," Nielsen said. By comparing the B. mandarina and B. mori genomes, he added, it was possible to get a window into the 5,000-year-old domestication process through resequencing.

"To me, that's what's been exciting," he said. "This has been the first large-scale resequencing project to look at this."

The researchers were able to gain additional insights by looking at genomes from each line. For instance, the team was surprised to find that although there were significant genetic differences between the wild and domestic strains, the genetic diversity was nearly as high in the domestic silkworms as it was in the wild ones.

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Past studies have shown that the domesticated versions of many organisms â€" including rice and wheat â€" have substantially lower levels of genetic variation than their wild counterparts. In contrast, the team found that the domestic worms had about 83 percent of the genetic variation found in wild strains.

The researchers still don't know exactly where silkworm domestication occurred. But given the genetic diversity found in present day domesticated silkworms, they concluded that there must have been sufficient diversity at the time to withstand the population bottlenecks and artificial selection pressure associated with domestication.

That, in turn, suggests domestication involved many silkworms from several places and that it happened quickly, Nielsen noted, perhaps spreading from one region to another.

The team also sifted through the genomes to find genes that appeared to be under strong selective pressure in the domesticated silkworms. In so doing, they found 1,041 "genomic regions of selective signals" â€" candidates for domestication-related genes â€" that comprised 2.9 percent of the domestic silkworm genome.

Within the so-called GROSS regions, the researchers identified 354 protein-coding genes that they believe may have contributed to domestication. When they compared this set of genes with those examined in silkworm expression studies, the team found that 159 GROSS genes are differentially expressed in certain tissues, including those that have been altered during domestication such as the silk gland, midgut, and testis.

"Genes in GROSS may comprise candidate targets under strong artificial selection and/or may be associated with the domestication of the silkworm," Wang told GWDN, calling their list "a starting point for candidate gene study in the future." The researchers hope that by finding and characterizing such genes, they will be able to hone in on the genetic underpinnings of both economically important traits as well as silkworm domestication.

"The silkmoth is an organism of great commercial interest," Nielsen said, pointing to its use for silk production, bioreactors, and the fact that wild silkworms are considered pests in many places.

Of particular interest is the silk gland factor-1 or Sgf-1 gene, which appears to have undergone a selective sweep in silkworms, Nielsen added. The gene codes for a protein that regulates the production of a glue protein in domestic silkworms, he explained, and is thought to regulate silk production.

Among the other candidates for artificial selection that the team is focusing on are three metabolism or reproduction-related genes whose expression is enriched in the midgut or testis.

None of the study's main conclusions could have been reached without taking a genome-wide approach, Nielsen said. And given the improvements in sequencing technology and decrease in sequencing cost, he believes this is the first of many studies like it.

The BGI researchers and their collaborators are currently using a similar resequencing approach â€" looking at many individual genomes from the same or related species â€" to get clues about the population genetics and evolutionary history of other types of organisms, including bacterial genomes and genomes for agriculturally important species. This spring, BGI obtained a dozen Illumina Genome Analyzers to bolster its sequencing capacity for efforts such as the Tree of Life Project (see In Sequence 4/21/2009).

The center's sequencing effort involves species with economic import, Wang said, but it is not limited to these organisms. For instance, Wang pointed to the panda genome, sequenced by BGI last year, and. noted that BGI researchers are currently investigating animals that can survive in extreme environmental conditions, such as the polar bear, penguin, and Tibetan antelope.

The team is mainly using, and developing software for, the Illumina Genome Analyzer, though Wang said that it is also trying out some sequencing with the ABI SOLiD and other platforms.

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