Human and mouse essentiality screens as a resource for disease gene discovery

The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery. Discovery of causal variants for monogenic disorders has been facilitated by whole exome and genome sequencing, but does not provide a diagnosis for all patients. Here, the authors propose a Full Spectrum of Intolerance to Loss-of-Function (FUSIL) categorization that integrates gene essentiality information to aid disease gene discovery

Kivu’s intractable security conundrum, revisited

‘The Security Problems of the Democratic Republic of Congo continue to puzzle international peace and policy makers’.1 This is how, in 2009, Koen Vlassenroot and Timothy Raeymaekers set out to explain conflict dynamics in the Kivu in this journal. They argued that while the peace process successfully unified the Congo and produced new, democratic institutions, it also led to the privatization of governance and the entrenching of conflicts. Within the new state structures, factionalized elites quickly began to exploit and feed insecurity as a means to leverage economic and political gain, often reproducing local struggles over power and historical grievances over land, identity, and economic marginalization.2 Misdiagnosing the Congolese state as failed, instead of deeply functional for a narrow elite, donors became complicit in the violence as these new elites drew on outside resources.3 Eight years on, much of Vlassenroot and Raeymaekers’ analysis remains highly relevant even as underlying dynamics have evolved. Since President Joseph Kabila’s contested re-election in 2011, the country has witnessed a steady deterioration of human security, most notably in the Kivus but also during the recent crisis in Kasai.4 Displacement has continued apace, reaching around 4.5 million—one of the highest levels ever recorded since the onset of the conflicts in 1993, with almost a million newly displaced in the first half of 2017 alone.5 At the same time, turmoil has engulfed national politics, as Kabila refused to step down at the end of his second constitutional term in 2016, delaying elections until the end of 2018, if not further. During this past decade, four developments have altered the contours of the conflict, contributing to a perpetuation of violence and insecurity. First, Congolese political and military elites have become increasingly invested in conflict, rendering it an end in itself. Instead of promoting cohesion and discipline, the government has perceived its security apparatus primarily as a means for distributing patronage, only occasionally prioritizing stability. Second, with the end of the Congrès national pour la défense du peuple (CNDP) rebellion in 2009, and more dramatically since the defeat of the Mouvement du 23 mars (M23) in 2013, regional involvement has decreased and the Kivus have seen few foreign-backed rebellions. This, combined with the national political crisis, has led armed groups to switch the focus of their bellicose rhetoric away from Rwanda towards Kinshasa. Third, there has been a dramatic proliferation of belligerents from a few dozens to over a hundred, while at the same time armed groups have coalesced into often unstable coalitions. Fourth, and most recently, insecurity is becoming increasingly politicized as political turmoil reverberates in the Kivus, prompting elites to bolster their influence through armed mobilization. Before analyzing these four trends in more detail, it is useful to provide an overview of key events in the past decade

Improved viability of populations with diverse life-history portfolios

A principle shared by both economists and ecologists is that a diversified portfolio spreads risk, but this idea has little empirical support in the field of population biology. We found that population growth rates (recruits per spawner) and life-history diversity as measured by variation in freshwater and ocean residency were negatively correlated across short time periods (one to two generations), but positively correlated at longer time periods, in nine Bristol Bay sockeye salmon populations. Further, the relationship between variation in growth rate and life-history diversity was consistently negative. These findings strongly suggest that life-history diversity can both increase production and buffer population fluctuations, particularly over long time periods. Our findings provide new insights into the importance of biocomplexity beyond spatio-temporal aspects of populations, and suggest that maintaining diverse life-history portfolios of populations may be crucial for their resilience to unfavourable conditions like habitat loss and climate change