Lee, P. | bioRxiv Science

bioRxiv2017

Forward-reverse mutation cycles between stages of cancer development

Earlier, prominent occurrences of interstitial loss-of-heterozygosities (LOHs) were found in different cancers as a type of single-nucleotide-variations (SNVs), at rates far exceeding those of the commonly investigated gain-of-heterozygosities (GOHs) type of SNVs. Herein, such co-occurrences of LOHs and GOHs were confirmed in 102 cases of four cancer types analyzed with three different next-generation sequencing platforms, comparing non-tumor, paratumor, and tumor tissues with white-blood-cell controls; and in 246 pan-cancer cases of whole-genome tumor-control pairs. Unexpectedly, large numbers of SNVs enriched with CG>TG GOHs and copy-number-variations (CNVs) proximal to these GOHs were detected in the non-tumor tissues, which were extensively reversed in paratumors showing prominent TG>CG LOHs with proximal CNVs, and less so in tumors to form forward-reverse mutation cycles. Lineage effects in the reversions, likely resulting from directional selection, supported a sequential rather than parallel mode of evolution as described in a Stage Specific Populations model of cancer development.

cancer biology↗

bioRxiv2017

Genetic validation of bipolar disorder identified by automated phenotyping using electronic health records

Bipolar disorder (BD) is a heritable mood disorder characterized by episodes of mania and depression. Although genomewide association studies (GWAS) have successfully identified genetic loci contributing to BD risk, sample size has become a rate-limiting obstacle to genetic discovery. Electronic health records (EHRs) represent a vast but relatively untapped resource for high-throughput phenotyping. As part of the International Cohort Collection for Bipolar Disorder (ICCBD), we previously validated automated EHR-based phenotyping algorithms for BD against in-person diagnostic interviews (Castro et al. 2015). Here, we establish the genetic validity of these phenotypes by determining their genetic correlation with traditionally-ascertained samples. Case and control algorithms were derived from structured and narrative text in the Partners Healthcare system comprising more than 4.6 million patients over 20 years. Genomewide genotype data for 3,330 BD cases and 3,952 controls of European ancestry were used to estimate SNP-based heritability (h2g) and genetic correlation(rg) between EHR-based phenotype definitions and traditionally-ascertained BD cases in GWAS by the ICCBD and Psychiatric Genomics Consortium (PGC) using LD score regression. We evaluated BD cases identified using 4 EHR-based algorithms: an NLP-based algorithm (95-NLP) and 3 rule-based algorithms using codified EHR with decreasing levels of stringency - \"coded-strict\", \"coded-broad\", and \"coded-broad based on a single clinical encounter\" (coded-broad-SV). The analytic sample comprised 862 95-NLP, 1,968 coded-strict, 2,581 coded-broad, 408 coded-broad-SV BD cases, and 3,952 controls. The estimated h2g were 0.24 (p=0.015), 0.09 (p=0.064), 0.13 (p=0.003), 0.00 (p=0.591) for 95-NLP, coded-strict, coded-broad and coded-broad-SV BD, respectively. The h2g for all EHR-based cases combined except coded-broad-SV (excluded due to 0 h2g) was 0.12 (p=0.004). These h2g were lower or similar to the h2g observed by the ICCBD+PGCBD (0.23, p=3.17E-80, total N=33,181). However, the rg between ICCBD+PGCBD and the EHR-based cases were high for 95-NLP (0.66, p=3.69x10-5), coded-strict (1.00, p=2.40x10-4), and coded-broad (0.74, p=8.11x10-7). The rg between EHR-based BDs ranged from 0.90 to 0.98. These results provide the first genetic validation of automated EHR-based phenotyping for BD and suggest that this approach identifies cases that are highly genetically correlated with those ascertained through conventional methods. High throughput phenotyping using the large data resources available in EHRs represents a viable method for accelerating psychiatric genetic research.

genetics↗

bioRxiv2017

Loss of MECP2 leads to telomere dysfunction and neuronal stress

To determine the role for mutations of MECP2 in Rett Syndrome, we generated isogenic lines of human iPSCs (hiPSCs), neural progenitor cells (NPCs), and neurons from patient fibroblasts with and without MECP2 expression in an attempt to recapitulate disease phenotypes in vitro. Molecular profiling uncovered neuronal specific gene expression changes including induction of a Senescence Associated Secretory Phenotype (SASP) program. Patient derived Neurons made without MECP2 show signs of stress, including induction of p53, and senescence. The induction of p53 appeared to affect dendritic branching in Rett neurons, as p53 inhibition restored dendritic complexity. These disease-in-a-dish data suggest that loss of MECP2 can lead to dendritic defects due to an increase in aspects of neuronal aging.

developmental biology↗