The Signature of Maternal Social Rank in Placenta Deoxyribonucleic Acid Methylation Profiles in Rhesus Monkeys.

The effects of social status on human health can be modeled in captive cohorts of nonhuman primates. This study shows that maternal social rank is associated with broad changes in DNA methylation in placentae of rhesus monkeys (N = 10). Differentially methylated genes between social ranks are enriched in signaling pathways playing major roles in placenta physiology. Moreover, the authors found significant overlaps with genes whose expression was previously associated with social rank in adult rhesus monkeys (Tung et al., 2012) and whose methylation was associated with perinatal stress in newborn humans and rhesus monkeys (Nieratschker et al., 2014). These results are consistent with the hypothesis that system-wide epigenetic changes in multiple tissues are involved in long-term adaptations to the social environment.

Early life adversity alters normal sex-dependent developmental dynamics of DNA methylation.

Studies in rodents, nonhuman primates, and humans suggest that epigenetic processes mediate between early life experiences and adult phenotype. However, the normal evolution of epigenetic programs during child development, the effect of sex, and the impact of early life adversity on these trajectories are not well understood. This study mapped the genome-wide DNA methylation changes in CD3+ T lymphocytes from rhesus monkeys from postnatal day 14 through 2 years of age in both males and females and determined the impact of maternal deprivation on the DNA methylation profile. We show here that DNA methylation profiles evolve from birth to adolescence and are sex dependent. DNA methylation changes accompany imposed weaning, attenuating the difference between males and females. Maternal separation at birth alters the normal evolution of DNA methylation profiles and targets genes that are also affected by a later stage maternal separation, that is, weaning. Our results suggest that early life events dynamically interfere with the normal developmental evolution of the DNA methylation profile and that these changes are highly effected by sex.

An integrated clinical program and crowdsourcing strategy for genomic sequencing and Mendelian disease gene discovery.

Despite major progress in defining the genetic basis of Mendelian disorders, the molecular etiology of many cases remains unknown. Patients with these undiagnosed disorders often have complex presentations and require treatment by multiple health care specialists. Here, we describe an integrated clinical diagnostic and research program using whole-exome and whole-genome sequencing (WES/WGS) for Mendelian disease gene discovery. This program employs specific case ascertainment parameters, a WES/WGS computational analysis pipeline that is optimized for Mendelian disease gene discovery with variant callers tuned to specific inheritance modes, an interdisciplinary crowdsourcing strategy for genomic sequence analysis, matchmaking for additional cases, and integration of the findings regarding gene causality with the clinical management plan. The interdisciplinary gene discovery team includes clinical, computational, and experimental biomedical specialists who interact to identify the genetic etiology of the disease, and when so warranted, to devise improved or novel treatments for affected patients. This program effectively integrates the clinical and research missions of an academic medical center and affords both diagnostic and therapeutic options for patients suffering from genetic disease. It may therefore be germane to other academic medical institutions engaged in implementing genomic medicine programs.

"Big Data" Gets Personal.

A woman at-risk for a rare fatal prion disease retrained in science with her husband and joined a bioinformatics team to analyze shared data, providing insights about variant penetrance and possible treatments (Minikel et al., this issue).

The executive prominent/memory prominent spectrum in Alzheimer's disease is highly heritable.

Late-onset Alzheimer's disease (LOAD) can present heterogeneously, with several subtypes recognized, including dysexecutive AD. One way to identify people with dysexecutive AD is to consider the difference between memory and executive functioning, which we refer to as the executive prominent/memory prominent spectrum. We aimed to determine if this spectrum was heritable. We used neuropsychological and genetic data from people with mild LOAD (Clinical Dementia Rating 0.5 or 1.0) from the National Alzheimer's Coordinating Center and the Alzheimer's Disease Neuroimaging Initiative. We cocalibrated the neuropsychological data to obtain executive functioning and memory scores and used their difference as a continuous phenotype to calculate its heritability overall and by chromosome. Narrow-sense heritability of the difference between memory and executive functioning scores was 0.68 (standard error 0.12). Single nucleotide polymorphisms on chromosomes 1, 2, 4, 11, 12, and 18 explained the largest fraction of phenotypic variance, with signals from each chromosome accounting for 5%-7%. The chromosomal pattern of heritability differed substantially from that of LOAD itself.