Wieczorek, D. | bioRxiv Science

bioRxiv2019

Scientific evaluation of negative exome sequencing followed by systematic scoring of candidate genes to decipher the genetics of neurodevelopmental disorders

BackgroundDeciphering the monogenetic causes of neurodevelopmental disorders (NDD) is an important milestone to offer personalized care. But the plausibility of reported candidate genes in exome studies often remains unclear, which slows down progress in the field.\n\nMethodsWe performed exome sequencing (ES) in 198 cases of NDD. Cases that remained unresolved (n=135) were re-investigated in a research setting. We established a candidate scoring system (CaSc) based on 12 different parameters reflecting variant and gene attributes as well as current literature to rank and prioritize candidate genes.\n\nResultsIn this cohort, we identified 158 candidate variants in 148 genes with CaSc ranging from 2 to 11.7. Only considering the top 15% of candidates, 14 genes were already published or funneled into promising validation studies.\n\nConclusionsWe promote that in an approach of case by case re-evaluation of primarily negative ES, systematic and standardized scoring of candidate genes can and should be applied. This simple framework enables better comparison, prioritization, and communication of candidate genes within the scientific community. This would represent an enormous benefit if applied to the tens of thousands of negative ES performed in routine diagnostics worldwide and speed up deciphering the monogenetic causes of NDD.

genetics↗

bioRxiv2018

The effect of ocean warming on black sea bass (Centropristis striata) aerobic scope and hypoxia tolerance

Over the last decade, ocean temperature in the U.S. Northeast Continental Shelf (U.S. NES) has warmed faster than the global average and is associated with observed distribution changes of the northern stock of black sea bass (Centropristis striata). Mechanistic models based on physiological responses to environmental conditions can improve future habitat suitability projections. We measured maximum, resting metabolic rate, and hypoxia tolerance (Scrit) of the northern adult black sea bass stock to assess performance across the known temperature range of the species. A subset of individuals was held at 30{degrees}C for one month (30chronic{degrees}C) prior to experiments to test acclimation potential. Absolute aerobic scope (maximum - resting metabolic rate) reached a maximum of 367.21 mgO2 kg-1 hr-1 at 24.4{degrees}C while Scrit continued to increase in proportion to resting metabolic rate up to 30{degrees}C. The 30chronic{degrees}C group had a significant decrease in maximum metabolic rate and absolute aerobic scope but resting metabolic rate or Scrit were not affected. This suggests a decline in performance of oxygen demand processes (e.g. muscle contraction) beyond 24{degrees}C despite maintenance of oxygen supply. The Metabolic Index, calculated from Scrit as an estimate of potential aerobic scope, closely matched the measured factorial aerobic scope (maximum / resting metabolic rate) and declined with increasing temperature to a minimum below 3. This may represent a critical value for the species. Temperature in the U.S. NES is projected to increase above 24{degrees}C in the southern portion of the northern stocks range. Therefore, these black sea bass will likely continue to shift north as the ocean continues to warm.

physiology↗