Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Hypopituitarism caused by blast-related mTBI may result in PTSD-like symptoms

Recent studies in civilian populations have found the prevalence of hypopituitarism as a result of head injuries from all causes to be between 25 and 50%. However, the neuroendocrine effects of concussion, or mild traumatic brain injury (mTBI) due to explosive blasts have received relatively little attention. Blast-related mTBI is the most common injury sustained by U.S. troops deployed to Iraq or Afghanistan. Approximately 20% of returning service members have experienced one or more blast-related concussions. Posttraumatic hypopituitarism (PTHP) has been shown to result in several symptoms that overlap considerably with those of PTSD. These include fatigue, depression, sexual dysfunction, anxiety, social isolation, and detrimental effects on sleep, learning and memory, body composition, and quality of life. We are investigating the prevalence of PTHP in two groups of Veterans of deployment to Iraq or Afghanistan. Members of the TBI group sustained at least one blast-related mTBI; members of the deployment control (DC) group experienced similar extreme conditions but did not experience a blast concussion. We conducted screening for growth hormone deficiency (GHD), hypogonadism, thyroid deficiency, and secondary adrenal insufficiency (sAI) by measuring basal blood samples and by testing for GHD and sAI with the glucagon stimulation test. Eighteen of 44 (36.4%) TBI group participants and seven of 32 (15.6%) DC group participants screened positive for pituitary hormone deficits. GHD and sAI were observed most frequently. We used behavioral self-reports and cognitive testing to examine symptom prevalence. Veterans with TBI and pituitary dysfunction endorsed more severe and/or frequent symptoms than those in the TBI group without hypopituitarism or the DC group. These findings and observations suggest that screening for pituitary dysfunction after head injuries holds promise for not only recognizing appropriate treatment options that might not otherwise be considered, but also facilitating recovery and rehabilitation of these service members.DoD CDMRP Concept Award PT090753 and VA RR&D Merit Award to CWW; Geriatric Research, Education and Clinical Center, and the Research and Development Service of the VA Puget Sound Health Care System; the VA Northwest Network Mental Illness Research, Education and Clinical Center; and the University of Washington Alzheimerʼs Disease Research Center NIA AG05136

Chronic Hypopituitarism Associated with Increased Postconcussive Symptoms Is Prevalent after Blast-Induced Mild Traumatic Brain Injury

The most frequent injury sustained by US service members deployed to Iraq or Afghanistan is mild traumatic brain injuries (mTBI), or concussion, by far most often caused by blast waves from improvised explosive devices or other explosive ordnance. TBI from all causes gives rise to chronic neuroendocrine disorders with an estimated prevalence of 25–50%. The current study expands upon our earlier finding that chronic pituitary gland dysfunction occurs with a similarly high frequency after blast-related concussions. We measured circulating hormone levels and accessed demographic and testing data from two groups of male veterans with hazardous duty experience in Iraq or Afghanistan. Veterans in the mTBI group had experienced one or more blast-related concussion. Members of the deployment control (DC) group encountered similar deployment conditions but had no history of blast-related mTBI. 12 of 39 (31%) of the mTBI participants and 3 of 20 (15%) veterans in the DC group screened positive for one or more neuroendocrine disorders. Positive screens for growth hormone deficiency occurred most often. Analysis of responses on self-report questionnaires revealed main effects of both mTBI and hypopituitarism on postconcussive and posttraumatic stress disorder (PTSD) symptoms. Symptoms associated with pituitary dysfunction overlap considerably with those of PTSD. They include cognitive deficiencies, mood and anxiety disorders, sleep problems, diminished quality of life, deleterious changes in metabolism and body composition, and increased cardiovascular mortality. When such symptoms are due to hypopituitarism, they may be alleviated by hormone replacement. These findings suggest consideration of routine post-deployment neuroendocrine screening of service members and veterans who have experienced blast-related mTBI and are reporting postconcussive symptoms