Inferring Admixture Histories of Human Populations Using Linkage Disequilibrium

Long-range migrations and the resulting admixtures between populations have been important forces shaping human genetic diversity. Most existing methods for detecting and reconstructing historical admixture events are based on allele frequency divergences or patterns of ancestry segments in chromosomes of admixed individuals. An emerging new approach harnesses the exponential decay of admixture-induced linkage disequilibrium (LD) as a function of genetic distance. Here, we comprehensively develop LD-based inference into a versatile tool for investigating admixture. We present a new weighted LD statistic that can be used to infer mixture proportions as well as dates with fewer constraints on reference populations than previous methods. We define an LD-based three-population test for admixture and identify scenarios in which it can detect admixture events that previous formal tests cannot. We further show that we can uncover phylogenetic relationships among populations by comparing weighted LD curves obtained using a suite of references. Finally, we describe several improvements to the computation and fitting of weighted LD curves that greatly increase the robustness and speed of the calculations. We implement all of these advances in a software package, ALDER, which we validate in simulations and apply to test for admixture among all populations from the Human Genome Diversity Project (HGDP), highlighting insights into the admixture history of Central African Pygmies, Sardinians, and Japanese.     

5,6-Dihydro-5-aza-2′-deoxycytidine potentiates the anti-HIV-1 activity of ribonucleotide reductase inhibitors

The nucleoside analog 5,6-dihydro-5-aza-2′-deoxycytidine (KP-1212) has been investigated as a first-in-class lethal mutagen of human immunodeficiency virus type-1 (HIV-1). Since a prodrug monotherapy did not reduce viral loads in Phase II clinical trials, we tested if ribonucleotide reductase inhibitors (RNRIs) combined with KP-1212 would improve antiviral activity. KP-1212 potentiated the activity of gemcitabine and resveratrol and simultaneously increased the viral mutant frequency. G-to-C mutations predominated with the KP-1212-resveratrol combination. These observations represent the first demonstration of a mild anti-HIV-1 mutagen potentiating the antiretroviral activity of RNRIs and encourage the clinical translation of enhanced viral mutagenesis in treating HIV-1 infection.     

Reconstructing Roma History from Genome-Wide Data

The Roma people, living throughout Europe and West Asia, are a diverse population linked by the Romani language and culture. Previous linguistic and genetic studies have suggested that the Roma migrated into Europe from South Asia about 1,000–1,500 years ago. Genetic inferences about Roma history have mostly focused on the Y chromosome and mitochondrial DNA. To explore what additional information can be learned from genome-wide data, we analyzed data from six Roma groups that we genotyped at hundreds of thousands of single nucleotide polymorphisms (SNPs). We estimate that the Roma harbor about 80% West Eurasian ancestry–derived from a combination of European and South Asian sources–and that the date of admixture of South Asian and European ancestry was about 850 years before present. We provide evidence for Eastern Europe being a major source of European ancestry, and North-west India being a major source of the South Asian ancestry in the Roma. By computing allele sharing as a measure of linkage disequilibrium, we estimate that the migration of Roma out of the Indian subcontinent was accompanied by a severe founder event, which appears to have been followed by a major demographic expansion after the arrival in Europe.     

Gardnerella vaginalis Subgroups Defined by cpn60 Sequencing and Sialidase Activity in Isolates from Canada,Belgium and Kenya

Increased abundance of Gardnerella vaginalis and sialidase activity in vaginal fluid is associated with bacterial vaginosis (BV), a common but poorly understood clinical entity associated with poor reproductive health outcomes. Since most women are colonized with G. vaginalis, its status as a normal member of the vaginal microbiota or pathogen causing BV remains controversial, and numerous classification schemes have been described. Since 2005, sequencing of the chaperonin-60 universal target (cpn60 UT) has distinguished four subgroups in isolate collections, clone libraries and deep sequencing datasets. To clarify potential clinical and diagnostic significance of cpn60 subgroups, we undertook phenotypic and molecular characterization of 112 G. vaginalis isolates from three continents. A total of 36 subgroup A, 33 B, 35 C and 8 D isolates were identified through phylogenetic analysis of cpn60 sequences as corresponding to four “clades” identified in a recently published study, based on sequencing 473 genes across 17 isolates. cpn60 subgroups were compared with other previously described molecular methods for classification of Gardnerella subgroups, including amplified ribosomal DNA restriction analysis (ARDRA) and real-time PCR assays designed to quantify subgroups in vaginal samples. Although two ARDRA patterns were observed in isolates, each was observed in three cpn60 subgroups (A/B/D and B/C/D). Real-time PCR assays corroborated cpn60 subgroups overall, but 13 isolates from subgroups A, B and D were negative in all assays. A putative sialidase gene was detected in all subgroup B, C and D isolates, but only in a single subgroup A isolate. In contrast, sialidase activity was observed in all subgroup B isolates, 3 (9%) subgroup C isolates and no subgroup A or D isolates. These observations suggest distinct roles for G. vaginalis subgroups in BV pathogenesis. We conclude that cpn60 UT sequencing is a robust approach for defining G. vaginalis subgroups within the vaginal microbiome.     

Optimizing return‐on‐effort for coral nursery and outplanting practices to aid restoration of the Great Barrier Reef

Coral nursery and outplanting practices have grown in popularity worldwide for targeted restoration of degraded “high value” reef sites, and recovery of threatened taxa. Success of these practices is commonly gauged from coral propagule growth and survival, which fundamentally determines the return‐on‐effort (RRE) critical to the cost‐effectiveness and viability of restoration programs. In many cases, RRE has been optimized from past successes and failures, which therefore presents a major challenge for locations such as the Great Barrier Reef (GBR) where no local history of restoration exists to guide best practice. In establishing the first multi‐taxa coral nursery on the GBR (Opal Reef, February 2018), we constructed a novel scoring criterion from concurrent measurements of growth and survivorship to guide our relative RRE, including nursery propagule numbers (stock density). We initially retrieved RRE scores from a database of global restoration efforts to date (n = 246; 52 studies) to evaluate whether and how success commonly varied among coral taxa. We then retrieved RRE scores for Opal Reef using initial growth and survivorship data for six key coral taxa, to demonstrate that RRE scores were high for all taxa predominantly via high survivorship over winter. Repeated RRE scoring in summer is therefore needed to capture the full dynamic range of success where seasonal factors regulating growth versus survivorship differ. We discuss how RRE scoring can be easily adopted across restoration practices globally to standardize and benchmark success, but also as a tool to aid decision‐making in optimizing future propagation (and outplanting) efforts.     

Beef production potential of Norwegian Red and Holstein-Friesian bulls slaughtered at two ages

There is a paucity of data on the beef production potential of Norwegian Red (NOR) compared with 'modern' Holstein-Friesian (HF) cattle. The present study used a total of 64 bulls in a 2 × 2 factorial design study encompassing two breeds (HF and NOR) and two slaughter ages (485; E, and 610; L, days). The mean initial age and live weight of the HF bulls were 179 (s.d. 47.1) days and 203 (s.d. 64.0) kg, while the corresponding data for the NOR bulls were 176 (s.d. 39.7) days and 185 (s.d. 63.6) kg, respectively. Bulls were offered a 50 : 50 mixture (dry matter (DM) basis) of grass silage and concentrates. No breed × slaughter group interactions were recorded for any parameters evaluated (P > 0.05). HF bulls had higher (P < 0.001) DM intake and poorer (P < 0.01) efficiency of conversion of food to carcass gain than NOR bulls. HF bulls tended (P = 0.07) to have a higher rate of live-weight gain and were heavier (P < 0.001) at slaughter than NOR bulls, though both carcass weight and rate of carcass gain did not differ between the breeds (P > 0.05). NOR bulls had higher (P < 0.001) dressing proportion and carcass conformation score than HF bulls, while breed of bull had no influence (P > 0.05) on carcass fat classification, depth of subcutaneous fat, marbling score or on the weight of fat in the internal depots. Daily food intakes did not differ (P > 0.05) across the two slaughter age groups, though efficiency of conversion of food to carcass gain was poorer (P < 0.05) in the L compared with E bulls. Rate of live-weight gain was lower (P < 0.01) for L bulls, although rate of carcass gain did not differ (P > 0.05) between the E and L bulls. Increasing age at slaughter increased (P < 0.01 or greater) dressing proportion, carcass fat class, depth of subcutaneous fat, marbling score and internal fat depots, but had no effect (P > 0.05) on the carcass conformation score. Instrumental measures of meat quality indicated that meat from NOR bulls was tougher (P < 0.01) than meat from HF bulls, while delaying slaughter increased (P < 0.001) a* and C*ab, and decreased (P < 0.01) h0, indicating improved redness. It is concluded that NOR bulls have higher food efficiency and produce more highly conformed carcasses than HF bulls, but HF bulls produce more tender meat.     

The role of echinocandins, extended-spectrum azoles, and polyenes to treat opportunistic moulds and Candida

Three classes of antifungals—polyenes, extended-spectrum azoles, and echinocandins—are now available for treating systemic fungal infections. Guidance for the appropriate use of this expanded variety of antifungals may come from recent clinical trials. Extended-spectrum azoles have excellent in vitro activity against Aspergillus and have been shown to improve clinical outcomes. For Zygomycetes, along with the lipid formulations of amphotericin, of the new agents, only posaconazole has activity. For Candida, the echinocandins offer a broad spectrum of activity. These new agents offer less toxicity and potentially improved efficacy in these difficult infections.     

A high-density admixture scan in 1,670 African Americans with hypertension

Hypertension (HTN) is a devastating disease with a higher incidence in African Americans than European Americans, inspiring searches for genetic variants that contribute to this difference. We report the results of a large-scale admixture scan for genes contributing HTN risk, in which we screened 1,670 African Americans with HTN and 387 control individuals for regions of the genome with elevated proportion of African or European ancestry. No loci were identified that were significantly associated with HTN. We also searched for evidence of an admixture signal at 40 candidate genes and eight previously reported linkage peaks, but none appears to contribute substantially to the differential HTN risk between African and European Americans. Finally, we observed nominal association at one of the loci detected in the admixture scan of Zhu et al. 2005 (p = 0.016 at 6q24.3 correcting for four hypotheses tested), although we caution that the significance is marginal and the estimated odds ratio of 1.19 per African allele is less than what would be expected from the original report; thus, further work is needed to follow up this locus.     

Neovascular age-related macular degeneration risk based on CFH, LOC387715/HTRA1, and smoking

Background

Age-related macular degeneration (AMD) is the major cause of blindness in the elderly. Those with the neovascular end-stage of disease have irreversible loss of central vision. AMD is a complex disorder in which genetic and environmental factors play a role. Polymorphisms in the complement factor H (CFH) gene, LOC387715, and the HTRA1 promoter are strongly associated with AMD. Smoking also contributes to the etiology. We aimed to provide a model of disease risk based on these factors.

Methods and Findings

We genotyped polymorphisms in CFH and LOC387715/HTRA1 in a case–control study of 401 patients with neovascular AMD and 266 controls without signs of disease, and used the data to produce genetic risk scores for the European-descent population based on haplotypes at these loci and smoking history. CFH and LOC387715/HTRA1 haplotypes and smoking status exerted large effects on AMD susceptibility, enabling risk scores to be generated with appropriate weighting of these three factors. Five common haplotypes of CFH conferred a range of odds ratios (ORs) per copy from 1 to 4.17. Most of the effect of LOC387715/HTRA1 was mediated through one detrimental haplotype (carriage of one copy: OR 2.83; 95% confidence interval [CI] 1.91–4.20), with homozygotes being at particularly high risk (OR 32.83; 95% CI 12.53–86.07). Patients with neovascular macular degeneration had considerably higher scores than those without disease, and risk of blinding AMD rose to 15.5% in the tenth of the population with highest predicted risk.

Conclusions

An individual''s risk of developing AMD in old age can be predicted by combining haplotype data with smoking status. Until there is effective treatment for AMD, encouragement to avoid smoking in those at high genetic risk may be the best option. We estimate that total absence of smoking would have reduced the prevalence of severe AMD by 33%. Unless smoking habits change or preventative treatment becomes available, the prevalence of AMD will rise as a consequence of the increasing longevity of the population.