Page 79 - The Welfare of Cattle

56 the WeLfare of CattLe

Figure 7.3 Genetically dehorned dairy calf gene edited to carry two copies of the dominant polled allele at the
POLLED locus. Picture by hannah smith Walker, Cornell alliance for science.

novel DNA sequence present in the genome of the edited animal that could not otherwise have been
produced using traditional breeding techniques. It is not evident what unique risks might be associ-
ated with an animal that is carrying the polled allele given the exact same sequence and resulting
phenotype that would be observed in the breed from which the allele sequence was derived.
It is possible that nucleases might introduce double-stranded breaks at locations other than the
target locus, and thereby introduce alterations elsewhere in the genome. Such off-target events are
analogous to spontaneous mutations which occur routinely, and can be minimized by careful design
of the gene-editing reagents.
Governments and regulators globally are currently deliberating about how or if gene-edited
animals should be regulated. In January 2017, the U.S. Food and Drug Administration’s draft
guidance for industry (GFI) #187 entitled “Regulation of Intentionally Altered Genomic DNA in
Animals” proposes to regulate all animals with “intentionally altered” DNA as drugs (FDA, 2017).
The guidance states that “intentionally altered genomic DNA may result from random or targeted
DNA sequence changes including nucleotide insertions, substitutions, or deletions”; however, it
clarifies selective breeding or other assisted reproductive technologies including random mutagen-
esis followed by phenotypic selection are not included as triggers. The new draft guidance then goes
on to state that

A specific DNA alteration is an article that meets the definition of a new animal drug at each site
in the genome where the alteration (insertion, substitution or deletion) occurs. The specific alteration
sequence and the site at which the alteration is located can affect both the health of the animals in the
lineage and the level and control of expression of the altered sequence, which influences its effective-
ness in that lineage. Therefore, in general, each specific genomic alteration is considered to be a sepa-
rate new animal drug subject to new animal drug approval requirements
This proposal to regulate genetic variants as drugs if they are intentionally induced seems to
trigger regulation of gene editing based on human intention rather than any unique risks associated
with the novel characteristics of the end product. It is known that each individual genome har-
bors many thousands of unique single nucleotide polymorphisms (SNPs), indels, and copy number
variants. For example, beef and milk contain enormous numbers of genetic variants that have accu-
mulated within the bovine gene pool because they are being introduced continually through natural
mutational processes. In one recent analysis of whole-genome sequence data from 234 taurine cattle
representing three breeds, >28 million variants were observed, comprising insertions, deletions, and