© 2002 Nature Publishing Group

For nearly 20 years, some sheephave flaunted what must be everyvain person’s dream: a geneticvariant that confers beautifulbuttocks, commonly known as thecallipyge phenotype. Moreprosaically, the single-locusmutation responsible for thephenotype causes musclehypertrophy, and it does sothrough an unusual genetic means,known as polar overdominance.This means that animals onlymanifest the phenotype if they areheterozygous for the callipygousvariant and only if the variant hasbeen inherited from a particularparent (in this case, the father).Freking and colleagues have nowpinpointed the single base changein the gene, CLPG, that underliesthe callipygous trait. Breeders andgeneticists alike have a stake in thisdiscovery: leaner meat could bebred as a result, and we could gaina better understanding of theepigenetic mechanisms thatunderlie the inheritance of thephenotype.

Previous efforts to map CLPGhad localized it genetically to asmall (400-kb) telomeric region onchromosome 18 — small enoughto make a direct-sequencingapproach to finding the variant arealistic goal. The high level ofbackground polymorphism insheep, however, made it impossibleto detect the causative SNP simplyby comparing affectedheterozygotes to normalhomozygotes. The authorstherefore turned to the pedigree ofthe particular flock they werestudying for some help. Onecallipygous ram in particular waskey: the critical region of bothcopies of chromosome 18 in thisram were probably identical-by-descent, apart from the presence ofthe CLPG mutation on one copy.Comparing the sequence of theram to a panel of informativegenotypes uncovered 616

polymorphisms, but only one ofthem — an A to G change — couldbe uniquely assigned to thecallipygous trait. The G allele wasnever found in sheep of diversebreeds, so validating further thepedigree-screening approach as themost robust there is for finding thecausative variant of a phenotype.

It’s taken ten years, but animportant aspect of the callipygephenotype has now been found,heralding the starting point forunderstanding what the CLPGvariant does. The CLPG region isconserved in cattle, human andmouse genomes, and the variantmight be incorporated into anRNA transcript, but little else isknown about its function. Initialattempts to detect whether thevariant has some regulatory effect— for example, by altering theimprinting status of the region —have been unsuccessful. Clearlymore work is needed to get to thebottom of this trait.

Tanita Casci

References and linksORIGINAL RESEARCH PAPER Freking, B. A. et al. Identification of the single base changecausing the callipyge muscle hypertrophyphenotype, the only known example of polaroverdominance in mammals. Genome Res. 12,1496–1506 (2002)

More than just apretty face

G E N E M A P P I N G

902 | DECEMBER 2002 | VOLUME 3 www.nature.com/reviews/genetics

H I G H L I G H T S

Public perceptions and regulatory policyThere are many reasons why the field of biotechnology isparticularly difficult to regulate. It is complex, the relevant sciencemoves forward quickly, and the risks and benefits that areassociated with it are not always easy to identify or agree on.However, I believe that the diverse and changing nature of publicperceptions stands as the single greatest regulatory challenge inthis area.

The international debate over “therapeutic cloning” is a goodexample of the dilemma. During the past few years, governmentsthroughout the world have been struggling with how best toregulate both reproductive and therapeutic cloning. Although the public clearly endorses a ban on reproductive cloning, theavailable opinion data on therapeutic cloning paints a morecomplex picture. Most research on public opinion has foundstrong support for stem-cell research and, even, a degree ofsupport for the concept of therapeutic cloning1. However, forsome citizens — about 20% in Canada — no amount of potentialsocial or scientific benefit will justify this type of research.As such, policy makers are left without a clear public mandate.Recently, the US President’s Council on Bioethics explicitly notedthis lack of consensus, and therefore concluded that a ban on allforms of human cloning was not justified and that a moratoriumshould be imposed to give time “to seek moral consensus”2.(I suspect that this “moral consensus” will remain elusive.)

Public opinion will also change. And, rightly or not, history tellsus that this change is likely to be in the direction of increasedpublic support (or, at least, increased ambivalence). In vitrofertilization, sperm donation, the transplantation of humanorgans and research involving cadavers were all activities thatwere first met with a degree of public resistance.

We should not make laws solely on the basis of opinion polls — a methodology with inherent limitations. However, we must alsoaccept that, for many areas of biotechnology, it will be difficult tojustify regulatory policy on broad consensus alone. I believe thatthe best way to deal with this inevitable state of affairs is to avoidthe use of rigid statutory prohibitions and, instead, to establishregulatory bodies with the power to oversee particular areas ofbiotechnology3. The regulatory body should be interdisciplinary,have the necessary expertise and a public engagement andeducation mandate, and be appropriately accountable. Whereasstatutory bans are often difficult to enact or change, a regulatoryapproach can accommodate emerging science and new social

concerns. And because a regulatorybody can serve as a forum forcontinuing public debate, it canremain sensitive to the public’smoral ambiguity concerning muchof biotechnology.

Timothy Caulfield

REFERENCES1Scoffield, H. Canadians favour limited use of clonesfor emergencies only, survey finds. Globe and MailA2, 16 June (2000) | 2The President’s Council onBioethics. Human Cloning and Human Dignity: AnEthical Inquiry (Washington, DC, July 2002) [online]<http://www.bioethics.gov/cloningreport/fullreport.html> | 3Knowles, L. Science policy and thelaw. Reproductive and therapeutic cloning. NYU J.Legis. Public Policy 4, 13 (2001)

ETHICS WATCH

Timothy Caulfield is at the Health LawInstitute at the University of Alberta,Canada.