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Genetic data from extant donkeys (Equus asinus) have revealed two distinct mitochondrial DNA haplogroups, suggestive of two separate domestication events in northeast Africa about 5000 years ago. Without distinct phylogeographic structure in domestic donkey haplogroups and with little information on the genetic makeup of the ancestral African wild ass, however, it has been difficult to identify wild ancestors and geographical origins for the domestic mitochondrial clades. Our analysis of ancient archaeological and historic museum samples provides the first genetic information on the historic Nubian wild ass (Equus africanus africanus), Somali wild ass (Equus africanus somaliensis) and ancient donkey. The results demonstrate that the Nubian wild ass was an ancestor of the first donkey haplogroup. In contrast, the Somali wild ass has considerable mitochondrial divergence from the Nubian wild ass and domestic donkeys. These findings resolve the long-standing issue of the role of the Nubian wild ass in the domestication of the donkey, but raise new questions regarding the second ancestor for the donkey. Our results illustrate the complexity of animal domestication, and have conservation implications for critically endangered Nubian and Somali wild ass.

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Abstract-Rats exposed chronically to mild cold (5°C/41°F) develop hypertension and cardiac hypertrophy. This provides a unique model of hypertension that is environmentally induced. The blood renin-angiotensin system (RAS) has been shown to play a role in both initiating and maintaining the high blood pressure (BP) in cold-induced hypertension. The mechanism also appears to involve both the tissue and brain RAS because there is increased mRNA for angiotensinogen (AGT) and angiotensin type 1 (AT 1 ) receptors in brain and peripheral tissues, an increased spontaneous drinking response, and an increased dipsogenic response to acute administration of angiotensin II (Ang II) in cold-treated rats. Key Words: hypertension, cold-induced Ⅲ angiotensinogen Ⅲ angiotensin II Ⅲ RNA Ⅲ receptors Ⅲ antisense elements R ats exposed to mild cold (5°C/41°F) develop hypertension. [1][2][3][4] This CIH is a nongenetic, nonsurgical model for studying hypertension in rats. Our previous studies have shown that the blood-borne RAS either prevents or attenuates CIH. 5,6 The mechanism also appears to involve both peripheral tissue and central RAS because there is increased mRNA for AGT and/or AT 1 -R in brain and peripheral tissues, 7 increased spontaneous drinking response, and increased dipsogenic response to acute administration of Ang II either centrally or subcutaneously. 8 The receptors for Ang II in the diencephalon of rats have been correlated directly with the drinking response to Ang II. 9,10 Furthermore, studies also suggest that there is a direct correlation between the state of receptors for Ang II in the diencephalon and development of hypertension, ie, upregulation of receptors for Ang II has been linked to the induction of both deoxycorticosterone acetate-salt and spontaneously induced hypertension. -13Tests of the dipsogenic responsiveness to Ang II, spontaneous drinking response to cold, and AT 1 -R mRNA in brain show much greater responses in cold-treated rats.8 This suggests that the receptors for Ang II are upregulated in rats exposed chronically to cold. Additional studies have shown an increased amount of mRNA for AGT, the substrate for the RAS, in the brains of cold-treated rats compared with rats kept at room temperature as controls. This raises the possibility that both increased production of Ang II and upregulation of Ang II receptors contribute to the elevation of BP during exposure to cold. An increased amount of mRNA of AGT and/or AT 1 -R in peripheral tissues (liver, adrenal glands, and aorta) of cold-treated rats suggests that an overactive peripheral tissue RAS is involved in CIH as well. AS-ODN, targeted to AGT mRNA or AT 1 -R mRNA, have been shown to reduce BP in SHR, which demonstrates that AS-ODN are specific and reduce an overactive RAS. 14 -18 Therefore, to assess more directly the role of the central RAS in CIH, AS-ODN to AGT mRNA and to AT 1 -R mRNA were

To produce a prolonged decrease m blood pressure, we have developed a nonpathogenic adeno-associated viral vector (AAV) with the antIsense DNA for AT1-R AAV has many advantages over other viral vectors AAV does not stimulate mflammallon or immune reaction AAV enters nondtvlchng cells and does not replicate Therefore, it IS an appropriate choice for gene therapy Recombinant AAV was prepared with a cassette contaumg a cytomegalovtrus promoter and the cDNA for the AT, receptor inserted m the annsense dire&on The cassette was packaged ohgonucleotides, directed to either AT,-R mRNA or to anglotensmogen mRNA, slgmfscantly reduce blood pressure m hypertensive animals with a single mJection mto the bram I-3 Although the adn-nmstration of antisense m the brain proved that antlsense can reduce high blood pressure of neurogemc orlgm, it obviously 1s not an acceptable route for treatment of human hypertension To demonstrate that antisense acts via a systemic route of delivery, we have shown that antisense delivered mtravenously4 or mtra-arterially5 can also reduce blood pressure m hypertensive rats. Antisense AT1 mRNA significantly decreased the blood pressure m 2&idney, 1 clip rats, m which circulating remn-Ang levels are high 4 Anglotensmogen mRNA-directed antIsense ohgonucleotide, in a hposome carrier inJected mtravenously m SHR, also decreased hypertension 5 The uptake of antisense was predommantly m the hver, as shown by fluorescent-tagged antisense. A sm-nlar approach was taken by Tomlta et al," who prepared three angiotensmogen mRNA-directed antisense ohgonucleotides and delivered them m hposomes and Sendal virus by direct mJectlon mto the hepatlc portal vem They also noted a decrease m blood pressure m SHR While these results have been encouraging for the use of antisense as a poFrom the Department of Physiology, College of Medicine, Unlversity of Florlda, Gamesvllle, Fla, and Harvard Medical School (P W ), Boston, MassCorrespondence to Dr M I Pixlhps, Department of Physiology, College of Medicine, Utuverslty of Flonda, Gamesvllle, FL 32610 E-mad MIP@phys med ufl edu 0 1997 American Heart Assoclatron, Inc tential treatment of hypertension, the maximum effectlveness of a single injection lasts for 7 days. Although this 1s Impressively longer than the response to a single dose of any antlhypertenslve drug currently available, it 1s our hope that we can extend the effectiveness of the antisense approach by delivering antisense m a viral vector that will produce a prolonged reduction m blood pressure for weeks or months There are several vu-al vectors to choose from, mcludmg retrovlruses, adenovlrus, herpes virus, polo virus, and AAV All have disadvantages and some advantages, but the AAV offers the most attractive advantages and the fewest disadvantages AAV 1s safe to use It does not induce any pathogenic response and does not replicate mslde cells The AAV 1s a defective parvovlrus and cannot replicate m cells without the presence of wild-type adenovlrus 73 The AAV IS effective as a vector because it either mt...