Or cOisogenic da an -fivefold reduction of Agrp RNA in the hypothalamus of AYla animals (Fig. 1C). We Expression of Agouti protein is normally limited to the skin where it affects pigmentation, also measured the levels of hypothalamic but ubiquitous expression causes obesity. An expressed sequence tag was identified Agrp RNA in oblob animals and found an that encodes Agouti-related protein, whose RNA is normally expressed in the hypoweightfold increase relative to coisogenic thalamus and whose levels were increased eightfold in oblob mice. Recombinant Agouticontrols. In the adrenal gland, levels of Agrp related protein was a potent, selective antagonist of Mc3r and Mc4r, melanocortin RNA in AYIa and nonmutant animals were receptor subtypes implicated in weight regulation. Ubiquitous expression of human below the level of detection, but could easily AGRP complementary DNA in transgenic mice caused obesity without altering pigmenbe detected in oblob animals. tation. Thus, Agouti-related protein is a neuropeptide implicated in the normal control ofTo determine whether AGRP antagobody weight downstream of leptin signaling.nizes melanocortin signaling, we used the baculovirus expression system to produce conditioned media containing recombinant human AGRP, and measured antag-Analysis of mouse obesity mutations has scriptase-polymerase chain reaction (RT-onist activity using a Xenopus melanohelped define regulatory circuits that gov-PCR) and Northern (RNA) hybridization phore cell line developed by Lerner and e m energy expenditure (1). In mice carry-experiments demonstrated that Agrp RNA colleagues (1 2). Melanophores provide a ing certain alleles of the Agouti coat color was expressed primarily in the adrenal gland rapid and sensitive bioassay for melanogene such as kthal yelow (A?) or YMbk and the hypothalamus (Fig. 1, B and C). To cortin agonists and antagonists because yellow (Aq), pleiotropic effects including a investigate functional overlap between Agrp pigment granule dispersion induced by ayellow coat, obesity, and increased body length are caused by ubiquitous expression a of chimeric transcripts encoding a normal A + ~o r m A B P -Agouti protein (2-4). Agouti is a paracrine ,,,,

SUMMARY The primate APOBEC3 gene locus encodes a family of proteins (APOBEC3A-H) with various antiviral and anti-retroelement activities. Here, we trace the evolution of APOBEC3H activity in hominoids to identify a human-specific loss of APOBEC3H antiviral activity. Reconstruction of the predicted ancestral human APOBEC3H protein shows that human ancestors encoded a stable form of this protein with potent antiviral activity. Subsequently, the antiviral activity of APOBEC3H was lost via two polymorphisms that are each independently sufficient to destabilize the protein. Nonetheless, an APOBEC3H allele that encodes a stably expressed protein is still maintained at high frequency, primarily in African populations. This stable APOBEC3H protein has potent activity against retroviruses and retrotransposons, including HIV and LINE-1 elements. The surprising finding that APOBEC3H antiviral activity has been lost in the majority of humans may have important consequences for our susceptibility to retroviral infections as well as ongoing retroelement proliferation in the human genome.