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International Team Publishes Findings from Phase One of 1,000 Bull Genomes Project

NEW YORK (GenomeWeb) – Members of an effort called the 1,000 bull genomes project have published findings from the first stage of that study — a whole-genome sequencing effort focused on 234 cattle from four breeds.

As they reported in Nature Genetics this weekend, the researchers sequenced 129 cattle from key ancestral representatives from the Holstein breed, 43 Fleckvieh breed ancestors, and 15 representatives ancestral to the Jersey cattle breed.

Together with existing genome sequence data for dozens of Angus cattle, the cattle genomes served as a source for finding more than 28 million cattle variants — SNPs and small insertions and deletions the team turned to in its search for genetic factors associated with favorable traits and cattle maladies.

"This information can immediately be deployed in breeding programs to reduce or eliminate such diseases and to improve the efficiency of beef and milk production," senior author Ben Hayes, a researcher with Australia's Department of Environment and Primary Industries, La Trobe University, and the Dairy Futures Cooperative Research Centre, and colleagues wrote.

"Further," they added, "the rapid identification of the mutations underlying sporadic syndromes that also occur in humans increases the attractiveness of cattle as models for such disease in the post-genomic era."

The 1,000 bull genome project is aimed at developing a variant database for understanding and predicting cattle traits that are not only important for milk and meat production, the team noted, but also for maintaining animal health and welfare when breeding and raising cattle.

By focusing on key ancestor bulls carrying chromosomal sequences found in most offspring from given cattle breeds, the researchers reasoned that they should be able to begin untangling complex traits in cattle in a relatively cost-effective manner.

"Once these ancestors are sequenced," they explained, "descendants need only be genotyped with a dense SNP array to accurately infer their genome sequence by tracing the large segments of chromosomes inherited from the ancestor bulls."

For the first stage of the project, investigators involved in the 1,000 bull genomes project began by sequencing 129 Holstein-Friesian key ancestors, 43 Fleckvieh breed key ancestors, and 15 Jersey breed key ancestors to average depths of 8.3-fold coverage apiece.

The cattle selected for the study, which were almost exclusively male, are believed to carry extensive stretches of ancestral chromosome sequences found in Holstein populations in Australia, France, and Denmark, Fleckvieh populations in Germany, and Australian Jersey cattle.

After folding in data for 47 Australian Angus cattle sequenced for a past selection study, the researchers went about searching for polymorphisms in the genomes, identifying 26.7 million SNPs and around 1.6 million indels. That variant set included 5.8 million SNPs and almost 141,000 indels previously detected in cattle, researchers reported, while the remaining SNPs were new.

In general, the team saw the most pronounced genetic overlap between the Holstein and Fleckvieh cattle, while the Angus and Jersey genomes tended to be most distinct from one another, sharing relatively few variants.

Through Illumina BeadChip genotyping on thousands more cattle, the researchers focused in on a recessively inherited mutation in a condensin complex-related gene called Smc2 that appears to cause embryonic loss, a fertility problem that can negatively impact beef and dairy operations.

Using the variant set identified with bull sequence data, the team also tied mutations in a Col2A1 gene to a recessively inherited form of chrondrodysplasia, a lethal condition in calves that's characterized by a cleft palate, short neck, and swollen skull.

The data proved useful for finding variants behind sought-after cattle traits as well. Along with association studies leading to variants contributing to milk production and early-lactation milk fat content in some of the cattle breeds, the researchers identified a mutation with ties to coat composition.

Using variant patterns imputed in more than 3,200 Fleckvieh bulls, they tracked down a Krt27 mutation coinciding with the presence of curly coat in that breed, a trait found in roughly 1 percent of Fleckvieh cattle that appears to make the animals more prone to parasites when kept in the pasture.

By continuing to sequence and genotype cattle, the study's authors argued, it should be possible to more quickly identify mutations behind conditions that are detrimental to animal health, while more effectively selecting for genomic features that enhance desirable cattle traits.

"Genomic selection is already being applied in cattle, but characterization of causal sequence variants will make genome selection much more robust than the use of markers," they concluded. "In the future, millions of cattle worldwide will be measured for complex traits and genotyped for SNP panels. The pedigree structure of cattle populations makes it possible to impute a full genome sequence for each of these genotyped individuals and to thus provide a discovery population with millions of animals, each with a genome sequence."

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