Andrew Masta

Genetic structure in village dogs reveals a Central Asian domestication origin

Significance Dogs were the first domesticated species, but the precise timing and location of domestication are hotly debated. Using genomic data from 5,392 dogs, including a global set of 549 village dogs, we find strong evidence that dogs were domesticated in Central Asia, perhaps near present-day Nepal and Mongolia. Dogs in nearby regions (e.g., East Asia, India, and Southwest Asia) contain high levels of genetic diversity due to their proximity to Central Asia and large population sizes. Indigenous dog populations in the Neotropics and South Pacific have been largely replaced by European dogs, whereas those in Africa show varying degrees of European vs. indigenous African ancestry. Dogs were the first domesticated species, originating at least 15,000 y ago from Eurasian gray wolves. Dogs today consist primarily of two specialized groups—a diverse set of nearly 400 pure breeds and a far more populous group of free-ranging animals adapted to a human commensal lifestyle (village dogs). Village dogs are more genetically diverse and geographically widespread than purebred dogs making them vital for unraveling dog population history. Using a semicustom 185,805-marker genotyping array, we conducted a large-scale survey of autosomal, mitochondrial, and Y chromosome diversity in 4,676 purebred dogs from 161 breeds and 549 village dogs from 38 countries. Geographic structure shows both isolation and gene flow have shaped genetic diversity in village dog populations. Some populations (notably those in the Neotropics and the South Pacific) are almost completely derived from European stock, whereas others are clearly admixed between indigenous and European dogs. Importantly, many populations—including those of Vietnam, India, and Egypt—show minimal evidence of European admixture. These populations exhibit a clear gradient of short-range linkage disequilibrium consistent with a Central Asian domestication origin.

Artemisinin-naphthoquine combination (ARCO™) therapy for uncomplicated falciparum malaria in adults of Papua New Guinea: A preliminary report on safety and efficacy

BackgroundThe use of anti-malarial drug combinations with artemisinin or with one of its derivatives is now widely recommended to overcome drug resistance in falciparum as well as vivax malaria. The fixed oral dose artemisinin-naphthoquine combination (ANQ, ARCO™) is a newer artemisinin-based combination (ACT) therapy undergoing clinical assessment. A study was undertaken to assess the safety, efficacy and tolerability of ANQ combination in areas of multi-drug resistance to generate preliminary baseline data in adult population of Papua New Guinea.MethodsThe clinical assessment was an open-labeled, two-arm, randomized study comparing ANQ combination as a single dose regimen and three days regimen (10 mg/kg/day) of chloroquine plus single dose sulphadoxine-pyrimethamine (CQ+SP) for the treatment of uncomplicated falciparum malaria with 28 days follow-up in an adult population. The primary outcome measures for efficacy were day 1, 2, 3 7, 14 and 28-day cure rates. Secondary outcomes included parasite clearance time, fever clearance time, and gametocyte carriage. The main outcome measures for safety were incidences of post-treatment clinical and laboratory adverse events.ResultsBetween June 2005 and July 2006, 130 patients with confirmed uncomplicated P. falciparum were randomly assigned to receive ANQ and CQ+SP, only 100 patients (51 in ANQ group and 49 in CQ+SP group) were evaluated for clinical and parasitological outcomes. All the patients treated with ANQ and CQ+SP showed adequate clinical and parasitological response with 28 days follow-up. The cure rate for ANQ on day 1, 2, 3, 7, 14, and 28 was 47%, 86%, 92%, 94%, 94% and 94%, respectively. Recrudescence account for 6%; all were cleared on day 21. For CQ+SP treated group the cure rates were 24%, 67%, 82%, 82%, 84% and 88%, respectively. Recrudescence accounted for 10%; all were cleared on day 28 except for one patient. Both regimens were well tolerated with no serious adverse events. The proportion of gametocyte carriers was higher in CQ+SP treated group than ANQ treatment (41% versus 12%; p < 0.05).ConclusionWhile these data are not themselves sufficient, it strongly suggests that the ANQ combination as a single dose administration is safe and effective for the treatment of uncomplicated P. falciparum malaria in the adult population of Papua New Guinea and deserves further clinical evaluation.

Genomic analysis of hepatitis B virus reveals antigen state and genotype as sources of evolutionary rate variation.

Hepatitis B virus (HBV) genomes are small, semi-double-stranded DNA circular genomes that contain alternating overlapping reading frames and replicate through an RNA intermediary phase. This complex biology has presented a challenge to estimating an evolutionary rate for HBV, leading to difficulties resolving the evolutionary and epidemiological history of the virus. Here, we re-examine rates of HBV evolution using a novel data set of 112 within-host, transmission history (pedigree) and among-host genomes isolated over 20 years from the indigenous peoples of the South Pacific, combined with 313 previously published HBV genomes. We employ Bayesian phylogenetic approaches to examine several potential causes and consequences of evolutionary rate variation in HBV. Our results reveal rate variation both between genotypes and across the genome, as well as strikingly slower rates when genomes are sampled in the Hepatitis B e antigen positive state, compared to the e antigen negative state. This Hepatitis B e antigen rate variation was found to be largely attributable to changes during the course of infection in the preCore and Core genes and their regulatory elements.

A cross-sectional study of reported symptoms for sexually transmissible infections among female sex workers in Papua New Guinea.

BACKGROUND Sexually transmissible infections (STIs) are common in female sex workers (FSWs), most of which are asymptomatic and therefore under-reported. Our aim was to determine the sensitivity and specificity of reported symptoms obtained via questionnaire augmented with leukocyte esterase (LE) urine dipstick test for the detection of Chlamydia trachomatis (Ct), Neisseria gonorrhea (Ng) and Trichomonas vaginalis (Tv) detected using polymerase chain reaction (PCR). METHODS In November 2003, a cohort of FSWs was screened for STIs and completed a questionnaire. RESULTS We enrolled 129 FSWs (90% participation rate) of whom 48 (37%), 30 (23%) and 53 (41%) were diagnosed with Ng, Ct and Tv, respectively, by PCR. Of those diagnosed with any of these infections, 78% reported anogenital symptoms and of those without infections, 28% reported symptoms. Anogenital symptoms were present in over 50% FSWs. Genital odour (present in 26%), lower abdominal pain (present in 29%), dysuria (present in 19%) had a sensitivity around (50%), specificity (>80%) and all were significantly associated with positive PCR results for individual organisms; however, the sensitivity of these symptoms to detect the presence of any positive PCR result was low (<50%). When LE urine dipstick test result of >1 was combined with the presence of three reported symptoms the sensitivity was 86%, specificity of 73% and a positive predictive value of 72%; a better predictor of infections. CONCLUSIONS Our finding suggest an approach that incorporates LE urine dipstick test >1 and multiple symptoms may be a feasible option for screening infections among FSWs in resource constraint settings.

Austronesian origin of the 27-bp deletion of the erythrocyte band 3 gene in East Sepik, Papua New Guinea inferred from mtDNA analysis

AbstractThe 27-bp deletion in the erythrocyte band 3 gene (B3Δ27) constitutes a genetic basis for Southeast Asian and Melanesian ovalocytosis. The distribution of B3Δ27 has been interpreted to reflect malaria selection or dispersal of the recent expansion of Austronesian-speaking populations. To explore these two hypotheses, we examined eight malarious populations of the East Sepik Province of Papua New Guinea (PNG) that speak both the Austronesian and Papuan languages. The B3Δ27 allele frequencies within populations were not positively correlated with malaria endemicities. In contrast, statistically significant geographical variations in the B3Δ27 allele distribution were observed. B3Δ27 was high (0.06-0.07) in the islands, intermediate (0.02-0.03) in coastal regions, but was absent or rare (0.00-0.01) in inland populations. Furthermore, the prevalence of the mitochondrial DNA region V 9-bp deletion, associated with the Austronesian expansion, was significantly correlated with that of B3Δ27. These results suggest that B3Δ27 was introduced by Austronesian-speaking people within the past 3,500 years and susequently expanded to populations along the coasts and islands of PNG. This study highlights the contribution of population origins, patterns of gene flow, disease selection and genetic drift in determining the genetic compositions of present populations.

Effects of periodic presumptive treatment on three bacterial sexually transmissible infections and HIV among female sex workers in Port Moresby, Papua New Guinea

BACKGROUND Sexually transmissible infections (STI) are common in female sex workers (FSW). AIM To determine if 3-monthly periodic presumptive treatments (PPT) would reduce the prevalence of STI in FSW. METHODS In a cohort study conducted between November 2003 and September 2004, FSW were enrolled, counselled and interviewed. Informed consent was obtained. Testing by using polymerase chain reaction (PCR) for Chlamydia trachomatis (Ct), Neisseria gonorrhoeae (Ng) and Trichomonas vaginalis (Tv), and serology for HIV were performed at baseline and final follow-up visits. Each FSW received 3-monthly oral amoxicillin, probenecid, a combination of amoxicillin and clavulanic acid, and azithromycin. Tinidazole was administered once. RESULTS The cohort consisted of 129 FSW at baseline and 71 at final follow-up visit. Of these 71 FSW, there was a significant decline in the proportion with positive PCR results for Ct from 38% to 16% (P=0.001), Ng from 56% to 23% (P=<0.001) and Tv from 62% to 30% (P=<0.001) between baseline and the final follow-up visit. HIV prevalence increased from 15% to 21% (P=0.125). CONCLUSIONS PPT was statistically effective in reducing STI but rates rebounded rapidly. Several new HIV infections occurred. If PPT is to be very effective in FSW where the prevalence of STI is so high, then 100% condom use with clients and regular sexual partners (RSP), and high rates of notification of RSP would be required if low incidence and prevalence of STI were to be achievable.

Infection frequency of hepatitis C virus and IL28B haplotypes in Papua New Guinea, Fiji, and Kiribati.

It has been estimated that there are more than 60 million Hepatitis C virus (HCV) carriers in the World Health Organisations Western Pacific region (WHO-WPR), where liver cancer is among the top three causes of cancer death. WHO and the US Centres for Disease Control and Prevention report the prevalence of HCV in the South Pacific islands (countries within the WHO-WPR) to be high (5–10% and >2% respectively). However, since HCV is not tested for in many of these countries, there is sparse data available to support this assertion. We screened ∼2000 apparently healthy individuals from Papua New Guinea, Fiji and Kiribati and found a sero-prevalence of 2.0%, 0.1% and 0%, respectively. All sero-positive samples tested negative for HCV RNA. Curious as to why all the sero-positive individuals were negative for HCV-RNA, we also screened them for the HCV protective IL28B SNP markers rs12979860 and rs8099917. All antibody-positive participants bar one had HCV protective haplotypes. Our results suggest that HCV is present in these Pacific island countries, albeit at a prevalence lower than previous estimates. As none of our participants had undergone antiviral treatment, and therefore must have cleared infection naturally, we hypothesise that genotypes 1 and/or 4 are circulating in South Pacific Island people and that these peoples are genetically predisposed to be more likely to spontaneous resolve HCV infection than to become chronic carriers.

Reply to Wang et al.: Sequencing datasets do not refute Central Asian domestication origin of dogs

We welcome the additional data and analyses of Wang et al. (1), but believe there are some misunderstandings regarding the methods and findings of Shannon et al. (2). First, although we merged Nepal and Mongolia when plotting linkage disequilibrium (LD) decay in figure 5B of ref. 2 for legibility, we did not assume Nepal and Mongolia represented a single, interbreeding population, and indeed computed separate LD scores for each population (figure 5A of ref. 2), matching Wang et al.’s (1) observation of slightly lower LD in Nepal than Mongolia. Although Nepal (along with India) is commonly considered part of South Asia, Nepal borders Central Asia. Dog populations in two Central Asian countries, Mongolia and Afghanistan, both have lower LD than India. Nepal does not border Southeast Asia. Because we cannot, given the resolution of current sampling … [↵][1]1To whom correspondence should be addressed. Email: arb359{at}cornell.edu. [1]: #xref-corresp-1-1