Is there indirect selection on female extra-pair reproduction through cross-sex genetic correlations with male reproductive fitness?

We thank Peter Arcese, Lukas Keller and Pirmin Nietlisbach for their support and long-term contributions to the dataset; the Tsawout and Tseycum First Nations bands for access to Mandarte; everyone who contributed to long-term data collection; and Greta Bocedi for helpful comments. JMR and MEW were funded by the European Research Council and NSERC (Canada) provided invaluable long-term support for the field study. The authors declare no conflict of interest. The doi for our data is 10.5061/dryad.p6df410.Peer reviewedPublisher PD

Determinants of successful clinical networks : The conceptual framework and study protocol

Background Clinical networks are increasingly being viewed as an important strategy for increasing evidence-based practice and improving models of care, but success is variable and characteristics of networks with high impact are uncertain. This study takes advantage of the variability in the functioning and outcomes of networks supported by the Australian New South Wales (NSW) Agency for Clinical Innovation's non-mandatory model of clinical networks to investigate the factors that contribute to the success of clinical networks. Methods/Design The objective of this retrospective study is to examine the association between external support, organisational and program factors, and indicators of success among 19 clinical networks over a three-year period (2006-2008). The outcomes (health impact, system impact, programs implemented, engagement, user perception, and financial leverage) and explanatory factors will be collected using a web-based survey, interviews, and record review. An independent expert panel will provide judgements about the impact or extent of each network's initiatives on health and system impacts. The ratings of the expert panel will be the outcome used in multivariable analyses. Following the rating of network success, a qualitative study will be conducted to provide a more in-depth examination of the most successful networks. Discussion This is the first study to combine quantitative and qualitative methods to examine the factors that contribute to the success of clinical networks and, more generally, is the largest study of clinical networks undertaken. The adaptation of expert panel methods to rate the impacts of networks is the methodological innovation of this study. The proposed project will identify the conditions that should be established or encouraged by agencies developing clinical networks and will be of immediate use in forming strategies and programs to maximise the effectiveness of such networks

Nonequivalent lethal equivalents : Models and inbreeding metrics for unbiased estimation of inbreeding load

We thank Peter Arcese, A. Bradley Duthie, Richard Frankham, Christine Grossen, Catherine Grueber, Marty Kardos, and three anonymous reviewers for helpful comments and discussion on earlier versions of this manuscript. We thank Cate Lessels and Peter Boag from whose 1987 paper in The Auk we copied the idea for the title of this paper. Our work was supported by a Swiss National Science Foundation grant (31003A-116794) to LFK, the Forschungskredit of the University of Zurich (FK-15-104) and a Swiss National Science Foundation grant (P2ZHP3_168447) to PN, and JMR was supported by a European Research Council grant.Peer reviewedPublisher PD

A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.3448Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H

Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial

Background: The EMPA KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population. Methods: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1·73 m2, or 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ≥40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1·73 m2, or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110. Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2·0 years (IQR 1·5–2·4). Prespecified subgroupings by primary kidney disease included 2057 (31·1%) participants with diabetic kidney disease, 1669 (25·3%) with glomerular disease, 1445 (21·9%) with hypertensive or renovascular disease, and 1438 (21·8%) with other or unknown causes. Kidney disease progression occurred in 384 (11·6%) of 3304 patients in the empagliflozin group and 504 (15·2%) of 3305 patients in the placebo group (hazard ratio 0·71 [95% CI 0·62–0·81]), with no evidence that the relative effect size varied significantly by primary kidney disease (pheterogeneity=0·62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1·37 mL/min per 1·73 m2 per year (95% CI 1·16–1·59), representing a 50% (42–58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all &gt;0·1). Interpretation: In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease. Funding: Boehringer Ingelheim, Eli Lilly, and UK Medical Research Council

Recombinant Haplotypes Narrow the ARMS2/HTRA1 Association Signal for Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is the leading cause of blindness in ageing societies, triggered by both environmental and genetic factors. The strongest genetic signal for AMD with odds ratios of up to 2.8 per adverse allele was found previously over a chromosomal region in 10q26 harboring two genes, ARMS2 and HTRA1, although with little knowledge as to which gene or genetic variation is functionally relevant to AMD pathology. In this study, we analyzed rare recombinant haplotypes in 16,144 AMD cases and 17,832 controls from the International AMD Genomics Consortium and identified variants in ARMS2 but not HTRA1 to exclusively carry the AMD risk with P-values between 1.0 x 10(-773) and 6.7 x 10(-5). This now allows prioritization of the gene of interest for subsequent functional studies

Female mating preferences and offspring survival: Testing hypotheses on the genetic basis of mate choice in a wild lekking bird

Indirect benefits of mate choice result from increased offspring genetic quality and may be important drivers of female behaviour. ‘Good-genes-for-viability’ models predict that females prefer mates of high additive genetic value, such that offspring survival should correlate with male attractiveness. Mate choice may also vary with genetic diversity (e.g. heterozygosity) or compatibility (e.g. relatedness), where the female's genotype influences choice. The relative importance of these nonexclusive hypotheses remains unclear. Leks offer an excellent opportunity to test their predictions, because lekking males provide no material benefits and choice is relatively unconstrained by social limitations. Using 12 years of data on lekking lance-tailed manakins, Chiroxiphia lanceolata, we tested whether offspring survival correlated with patterns of mate choice. Offspring recruitment weakly increased with father attractiveness (measured as reproductive success, RS), suggesting attractive males provide, if anything, only minor benefits via offspring viability. Both male RS and offspring survival until fledging increased with male heterozygosity. However, despite parent–offspring correlation in heterozygosity, offspring survival was unrelated to its own or maternal heterozygosity or to parental relatedness, suggesting survival was not enhanced by heterozygosity per se. Instead, offspring survival benefits may reflect inheritance of specific alleles or nongenetic effects. Although inbreeding depression in male RS should select for inbreeding avoidance, mates were not less related than expected under random mating. Although mate heterozygosity and relatedness were correlated, selection on mate choice for heterozygosity appeared stronger than that for relatedness and may be the primary mechanism maintaining genetic variation in this system despite directional sexual selection

Disentangling the effect of genes, the environment and chance on sex ratio variation in a wild bird population

Sex ratio theory proposes that the equal sex ratio typically observed in birds and mammals is the result of natural selection. However, in species with chromosomal sex determination, the same 1 : 1 sex ratio is expected under random Mendelian segregation. Here, we present an analysis of 14 years of sex ratio data for a population of song sparrows (Melospiza melodia) on Mandarte Island, at the nestling stage and at independence from parental care. We test for the presence of variance in sex ratio over and above the binomial variance expected under Mendelian segregation, and thereby quantify the potential for selection to shape sex ratio. Furthermore, if sex ratio variation is to be shaped by selection, we expect some of this extra-binomial variation to have a genetic basis. Despite ample statistical power, we find no evidence for the existence of either genetic or environmentally induced variation in sex ratio, in the nest or at independence. Instead, the sex ratio variation observed matches that expected under random Mendelian segregation. Using one of the best datasets of its kind, we conclude that female song sparrows do not, and perhaps cannot, adjust the sex of their offspring. We discuss the implications of this finding and make suggestions for future research

Additive genetic variance, heritability, and inbreeding depression in male extra-pair reproductive success

The hypothesis that female extra-pair reproduction in socially monogamous animals reflects indirect genetic benefits requires that there be additive and/or nonadditive genetic variance in fitness. However, the specific hypotheses that male extra-pair reproductive success (EPRS) shows additive genetic variance (VA), heritability (h(2)), or inbreeding depression, and hence that females could acquire indirect genetic benefits through increased EPRS of sons, have not been explicitly tested. We used comprehensive genetic pedigree data from song sparrows (Melospiza melodia) to estimate V(A), h(2), and inbreeding depression in the number of extra-pair offspring a male sired per year and the probability that a male would sire any extra-pair offspring per year. Inbreeding depression was substantial: more inbred males sired fewer extra-pair offspring and were less likely to sire any extra-pair offspring. In contrast, estimates of V(A) and h(2) were close to 0, although 95% credible intervals were relatively wide. These data suggest that females could accrue indirect genetic benefits, in terms of increased EPRS of outbred sons, by mating with unrelated social or extra-pair mates. In contrast, any indirect benefit of extra-pair reproduction in terms of producing sons with high additive genetic value for EPRS is most likely to be small