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Sheep Researchers Design High-Density SNP Chip to Support GWAS, Genomic Selection

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Scientists who study sheep now have a new tool at their disposal.

This month, the International Sheep Genomics Consortium, Illumina, and FarmIQ announced the completion of the Ovine Infinium HD SNP BeadChip. With 600,000 markers, the new array complements Illumina's 50,000-marker OvineSNP50 BeadChip. It also is one of a handful of high-density SNP chips produced to date for agricultural research.

Both Illumina and Affymetrix have commercialized high-density arrays for bovine studies. Affymetrix has also commercialized a high-density array for studying chicken (BAN 1/24/2012).

An Illumina spokesperson told BioArray News this week that the firm has no immediate plans to make a catalog version of the Ovine Infinium HD available. Instead, the spokesperson said that interested researchers can contact the ISGC directly if they wish to obtain access to the new chips.

Illumina's catalog OvineSNP50 has been widely adopted by sheep researchers, notably in a 2012 study that produced a map of global sheep genetic diversity (BAN 2/28/2012).

Still, a higher-density chip was necessary to include new content at a density to be useful for genome-wide association studies, as well as to identify new markers that could be used in the genomic selection of animals for breeding, according to John McEwan, a senior scientist at AgResearch, a state-owned research institute in New Zealand.

"The primary need for the [high-density] ovine array was that the original 50K array built in 2009 was created on an early genome assembly, so it had a number of gaps," McEwan told BioArray News.

Based on OvineSNP50 data, AgResearch has also designed a lower-density custom 6,000 SNP array, McEwan said. Based on 6K chip data, breeders can impute OvineSNP50 markers in order to select rams for breeding.

Given its density and cost, McEwan said that the new Ovine Infinium HD array is "unlikely to be implemented in any but very specialized breeding operations."

Another issue is that most breeding programs in New Zealand rely on a statistical method called genomic best linear unbiased prediction, or GBLUP, to estimate the proportion of the genome shared between individuals, McEwan said. To make decisions informed by GBLUP, breeders need between 5,000 and 20,000 SNP markers at most, not the 600,000 included on the Ovine Infinium HD, he said.

At the same time, McEwan said that, considering their content, these lower-density chips have "significant limitations" as research tools. Because of this, McEwan and fellow researchers will use the new Ovine Infinium HD chip to "identify, track, and utilize variants" to make better informed breeding decisions. To identify such markers, they will conduct association studies using the chips, and new variants will then be used to inform the design of future, lower-density arrays, like the 6K, that are used directly in selection.

"I would expect the most obvious initial use is to take the small number of variants identified and simply add them to the low-density chip and tweak the analysis," said McEwan. "This gets the majority of benefits and minimal additional cost to the commercial user."

Development and design

FarmIQ, a joint New Zealand government and industry partnership program, funded the development of the Ovine Infinium HD, according to a FarmIQ statement. Illumina was selected as the genotyping platform provider "after evaluation of the various technologies available," FarmIQ said.

Baylor College of Medicine's Human Genome Sequencing Center sequenced the whole genomes of 75 individual sheep from a variety of breeds as part of the chip development process. DNA samples and measurements were also taken from 12,000 New Zealand lamb carcasses, the partners said.

Teams at AgResearch, BCM, the US Department of Agriculture, the Department of Primary Industries Victoria in Australia, and Australia's Commonwealth Scientific and Industrial Research Organization, then collaborated to identify more than 20 million sheep gene sequence variants, which were then filtered down to produce the Ovine Infinium HD.

McEwan said that the chip was designed with "three levels" of interest in mind. The first level was to aid FarmIQ's efforts to develop branded product lamb supply chains, with a focus on the carcass and meat quality of New Zealand lambs, he said. The second level was based on input from the ISGC, and the third level of interest came from Baylor, CSIRO, DPIVic, and AgResearch — the organizations that led the development of the array.

According to McEwan, the resulting chip is one of the first [livestock-focused] chips that has been designed after a significant number of animals have been sequenced and a high-quality assembly available."

The array consists of a number of overlapping components, he said. In total, there are 694,125 oligonucleotudes representing 685,734 SNPs. "This leaves a small headspace for the addition of custom oligos at a later date," McEwan said.

The majority of SNPs selected were spaced equally across the genome and selected from groups differing in their minor allele frequency across an international sample of breeds that had been sequenced to 10X coverage, McEwan added. The chip also includes minor groups of SNPs including those reported in the literature as being functional and those SNPs that change the amino acid sequences of proteins, he said.

Some 606,006 SNPs passed manufacturing quality control, and on validation 603,350 SNPs had callable results with a mean call rate of 99.75 percent, according to McEwan. Also, in a sample of the New Zealand lamb population, 536,373 SNPs had a minor allele frequency of greater than 0.05, he said.

"This is a very high success rate given that some 30,328 non-synonymous SNPs had been included in the design with an estimated minor allele frequency of less than 10 percent because they caused functional changes in proteins and even at low frequency they may have important commercial impact," McEwan noted.

McEwan said that the tool is being used initially in New Zealand for detailed studies of carcass and meat quality, but it has already been used by separate organizations for a variety of non-farm traits including investigation into the host genetics of methane emissions.

A number of international groups are also using the new HD chip for studies focused on dairy sheep. "We expect one early emphasis will be on identification of loss of function mutations that have up until now caused production losses in difficult to measure traits," McEwan said of these early studies.

Cindy Lawley, Illumina’s global agriculture consortia program manager, told BioArray News that the Ovine Infinium HD is available directly from AgResearch and the ISGC. She confirmed that the array is already being used by ISGC researchers "as one of our many private consortium chips available through Illumina’s AgConsortia Program."

Lawley added that the Ovine Infinium HD contains "marker densities suitable for whole genome selection, copy number variant analysis, and for establishing diversity estimates that allow for imputation to the whole genome for genomic breed evaluation." She also said that the firm sees the chips as an alternative to other approaches.

"These arrays are a lower cost alternative to whole-genome sequencing and are being implemented on high value animals along with complementary genotyping using lower density tools like AgResearch’s low-density [6K] sheep chip to characterize the entire herd or flock," Lawley said.

Illumina currently makes consortia-designed SNP chips of varying densities for over a dozen animals and plants. A full listing of chips designed to date is available on the company's website.

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