Mitochondrial genome variants associated with amyotrophic lateral sclerosis and their haplogroup distribution.

INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) may be familial or sporadic, and twin studies have revealed that even sporadic forms have a significant genetic component. Variants in 55 nuclear genes have been associated with ALS and although mitochondrial dysfunction is observed in ALS, variants in mitochondrial genomes (mitogenomes) have not yet been tested for association with ALS. The aim of this study was to determine whether mitogenome variants are associated with ALS. METHODS: We conducted a genome-wide association study (GWAS) in mitogenomes of 1965 ALS patients and 2547 controls. RESULTS: We identified 51 mitogenome variants with p values <10-7, of which 13 had odds ratios (ORs) >1, in genes RNR1, ND1, CO1, CO3, ND5, ND6, and CYB, while 38 variants had OR <1 in genes RNR1, RNA2, ND1, ND2, CO2, ATP8, ATP6, CO3, ND3, ND4, ND5, ND6, and CYB. The frequencies of haplogroups H, U, and L, the most frequent in our ALS data set, were the same in different onset sites (bulbar, limb, spinal, and axial). Also, intra-haplogroup GWAS revealed unique ALS-associated variants in haplogroups L and U. DISCUSSION: Our study shows that mitogenome single nucleotide variants (SNVs) are associated with ALS and suggests that these SNVs could be included in routine genetic testing for ALS and that mitochondrial replacement therapy has the potential to serve as a basis for ALS treatment.

Homeostasis in networks with multiple inputs.

Homeostasis, also known as adaptation, refers to the ability of a system to counteract persistent external disturbances and tightly control the output of a key observable. Existing studies on homeostasis in network dynamics have mainly focused on 'perfect adaptation' in deterministic single-input single-output networks where the disturbances are scalar and affect the network dynamics via a pre-specified input node. In this paper we provide a full classification of all possible network topologies capable of generating infinitesimal homeostasis in arbitrarily large and complex multiple inputs networks. Working in the framework of 'infinitesimal homeostasis' allows us to make no assumption about how the components are interconnected and the functional form of the associated differential equations, apart from being compatible with the network architecture. Remarkably, we show that there are just three distinct 'mechanisms' that generate infinitesimal homeostasis. Each of these three mechanisms generates a rich class of well-defined network topologies-called homeostasis subnetworks. More importantly, we show that these classes of homeostasis subnetworks provides a topological basis for the classification of 'homeostasis types': the full set of all possible multiple inputs networks can be uniquely decomposed into these special homeostasis subnetworks. We illustrate our results with some simple abstract examples and a biologically realistic model for the co-regulation of calcium ( Ca ) and phosphate ( PO 4 ) in the rat. Furthermore, we identify a new phenomenon that occurs in the multiple input setting, that we call homeostasis mode interaction, in analogy with the well-known characteristic of multiparameter bifurcation theory.

Reconstructing Prehistoric Viral Genomes from Neanderthal Sequencing Data.

DNA viruses that produce persistent infections have been proposed as potential causes for the extinction of Neanderthals, and, therefore, the identification of viral genome remnants in Neanderthal sequence reads is an initial step to address this hypothesis. Here, as proof of concept, we searched for viral remnants in sequence reads of Neanderthal genome data by mapping to adenovirus, herpesvirus and papillomavirus, which are double-stranded DNA viruses that may establish lifelong latency and can produce persistent infections. The reconstructed ancient viral genomes of adenovirus, herpesvirus and papillomavirus revealed conserved segments, with nucleotide identity to extant viral genomes and variable regions in coding regions with substantial divergence to extant close relatives. Sequence reads mapped to extant viral genomes showed deamination patterns of ancient DNA, and these ancient viral genomes showed divergence consistent with the age of these samples (≈50,000 years) and viral evolutionary rates (10-5 to 10-8 substitutions/site/year). Analysis of random effects showed that the Neanderthal mapping to genomes of extant persistent viruses is above what is expected by random similarities of short reads. Also, negative control with a nonpersistent DNA virus does not yield statistically significant assemblies. This work demonstrates the feasibility of identifying viral genome remnants in archaeological samples with signal-to-noise assessment.