Genome-Wide Association Study of Relative Telomere Length

Telomere function is essential to maintaining the physical integrity of linear chromosomes and healthy human aging. The probability of forming proper telomere structures depends on the length of the telomeric DNA tract. We attempted to identify common genetic variants associated with log relative telomere length using genome-wide genotyping data on 3,554 individuals from the Nurses' Health Study and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial that took part in the National Cancer Institute Cancer Genetic Markers of Susceptibility initiative for breast and prostate cancer. After genotyping 64 independent SNPs selected for replication in additional Nurses' Health Study and Women's Genome Health Study participants, we did not identify genome-wide significant loci; however, we replicated the inverse association of log relative telomere length with the minor allele variant [C] of rs16847897 at the TERC locus (per allele β = −0.03, P = 0.003) identified by a previous genome-wide association study. We did not find evidence for an association with variants at the OBFC1 locus or other loci reported to be associated with telomere length. With this sample size we had >80% power to detect β estimates as small as ±0.10 for SNPs with minor allele frequencies of ≥0.15 at genome-wide significance. However, power is greatly reduced for β estimates smaller than ±0.10, such as those for variants at the TERC locus. In general, common genetic variants associated with telomere length homeostasis have been difficult to detect. Potential biological and technical issues are discussed

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

An integrated multi-omic analysis of iPSC-derived motor neurons from C9ORF72 ALS patients

Neurodegenerative diseases are challenging for systems biology because of the lack of reliable animal models or patient samples at early disease stages. Induced pluripotent stem cells (iPSCs) could address these challenges. We investigated DNA, RNA, epigenetics, and proteins in iPSC-derived motor neurons from patients with ALS carrying hexanucleotide expansions in C9ORF72. Using integrative computational methods combining all omics datasets, we identified novel and known dysregulated pathways. We used a C9ORF72 Drosophila model to distinguish pathways contributing to disease phenotypes from compensatory ones and confirmed alterations in some pathways in postmortem spinal cord tissue of patients with ALS. A different differentiation protocol was used to derive a separate set of C9ORF72 and control motor neurons. Many individual -omics differed by protocol, but some core dysregulated pathways were consistent. This strategy of analyzing patient-specific neurons provides disease-related outcomes with small numbers of heterogeneous lines and reduces variation from single-omics to elucidate network-based signatures

PERISCOPE: road towards effective control of pertussis

The resurgence and changing epidemiology of pertussis in high-income countries, the high infant mortality caused by pertussis in low-income countries, and the increasing morbidity in all age groups worldwide call for a concerted effort to both improve the current vaccines and develop new vaccines and vaccination strategies against pertussis. In this Personal View, we identify several key obstacles on the path to developing a durable solution for global control of pertussis. To systematically address these obstacles, the PERtussIS Correlates Of Protection Europe ( PERISCOPE) Consortium was established in March, 2016. The objectives of this consortium are to increase scientific understanding of immunity to pertussis in humans induced by vaccines and infections, to identify biomarkers of protective immunity, and to generate technologies and infrastructure for the future development of improved pertussis vaccines. By working towards the accelerated licensure and implementation of novel, well tolerated, and effective pertussis vaccines, we hope to strengthen and stimulate further collaboration and transparency between the key stakeholders, including the public, the scientific community, public health institutes, regulatory authorities, and vaccine manufacturers.Stemcel biology/Regenerative medicine (incl. bloodtransfusion

Genomic Approaches for Climate Resilience Breeding in Oats

Editors: Chittaranjan Kole.Oat (Avena sativa L.), ranking sixth in world cereal production, is primarily produced as a multipurpose crop for grain, pasture, and forage or as a rotation crop in many parts of the world. Recent research has elevated its potential dietary value for human nutrition and health care. Oats are well adapted to a wide range of soil types and can perform on acid soils. World oat production is concentrated between latitudes 35–65º N, and 20–46º S. Avena genomes are large and complex, in the range of 4.12–12.6 Gb. Oat productivity is affected by many diseases, although crown rust (Puccinia coronate f. sp. avenae) and stem rust (Puccinia graminis f. sp. avenae) are the key diseases worldwide. The focus of this chapter is to review the major developments and their impacts on oat breeding, especially on the challenges posed by climate or environmental changes (biotic and abiotic stresses mainly) for oat cultivation. Next-generation breeding tools will help to develop approaches to genetically improve and manipulate oat which would aid significantly in oat enhancement efforts. Although, oat biotechnology has been advanced at a similar pace as the rest of cereals, it lags still behind. More genomic tools, from genomic assisted breeding to genome editing tools are needed to improve the resources to improve oats under climate change in the next few decades