Yaping Liu, PhD

FinaleDB: a browser and database of cell-free DNA fragmentation patterns.

Circulating cell-free DNA (cfDNA) is a promising biomarker for the diagnosis and prognosis of many diseases, including cancer. The genome-wide non-random fragmentation patterns of circulating cell-free DNA (cfDNA)are associated with the nucleosomal protection, epigenetic environment and gene expression in the cell types that contributed to cfDNA. However, current progress on the development of computational methods and understanding of molecular mechanisms behind cfDNA fragmentation patterns is significantly limited by the controlled-access of cfDNA whole-genome sequencing (WGS) dataset. To address this challenge, we developed FinaleDB (FragmentatIoN AnaLysis of cEll-free DNA DataBase), a comprehensive database to host thousands of uniformly processed and curated de-identified cfDNA WGS datasets across different pathological conditions. Furthermore, FinaleDB comes with a fragmentation genome browser, from which users can seamlessly integrate thousands of other omics data in different cell types to experience a comprehensive view of both gene-regulatory landscape and cfDNA fragmentation patterns.

Ge Zhang, PhD

Dissecting maternal and fetal genetic effects underlying the associations between maternal phenotypes, birth outcomes, and adult phenotypes: A mendelian-randomization and haplotype-based genetic score analysis in 10,734 mother-infant pairs.

Many maternal traits associate with a neonate’s gestational duration, birth weight, and birth length. These birth outcomes subsequently associate with late-onset health conditions. There is no resolution of the causal mechanisms and the relative contributions of maternal and fetal genetic effects behind these observed associations. In the study, we utilized an innovative genomic approach (i.e. haplotype-based genetic score analysis) and we studied the maternal and fetal genetic effects underlying the observed associations between maternal phenotypes and pregnancy outcomes in over 10,000 mother-infant pairs. We found that many genetic variants associated with maternal height, blood pressure, and blood glucose levels (or type 2 diabetes susceptibility) can have various maternal and fetal genetic effects on gestational duration and fetal growth. These maternal and fetal genetic effects largely explain the observed associations between the maternal phenotypes and birth outcomes, as well as the life-course associations between these birth outcomes and adult phenotypes. Our findings also suggest that rapid fetal growth might reduce gestational duration and increase maternal blood pressure. These findings provide additional insights into the mechanisms behind the observed associations between maternal phenotypes and birth outcomes and their life-course impacts on later-life health.

Lindsey Barske, PhD

Evolution of vertebrate gill covers via shifts in an ancient Pou3f3 enhancer.

Branchial cleft fistulae are the most common source of congenital neck masses in children. These vestigial openings between the pharynx and the external environment are normally sealed off during development when the hyoid arch grows over the posterior pharyngeal arches to fuse with the upper trunk. In fish, this fusion does not occur, and the overgrown hyoid arch instead forms the gill cover, a musculoskeletal appendage that drives oxygenated water over the gills. In a study published in the Proceedings of the National Academy of Sciences, Barske, et al. identify Pou3f3 as the first gene essential for the formation of gill covers in modern vertebrates. Using zebrafish, mouse, little skate, elephant shark, and jawless lamprey species as models, they further uncover the genomic element that brought Pou3f3 expression into the pharynx more than 430 Mya. Remarkably, small changes in this deeply conserved sequence account for the single large gill cover present in living bony fish versus the five separate covers of sharks and their brethren. Understanding how Pou3f3 controls gill cover formation will provide insight into how disruptions to the homologous process in humans can manifest as branchial cleft fistulae in children.

Cindy Prows, MSN, CNS

Participant choices for return of genomic results in the eMERGE Network.

Ten Network sites used a sequencing panel of ~100 genes during phase III of the Electronic Medical Records and Genomics Network. Through a consensus process, network experts designated 67 genes and 14 SNVs as returnable. Five sites offered research participants (n = 4664) choices about which gene results they wanted to learn. We demonstrated that up to 20% of participants across five sites chose to learn some but not all potential results. Our study highlighted different sites’ strategies to operationalize participant choices and consequent variation in choice outcomes. Most laboratories allow patients to choose to learn all or none of a set of genes recommended by the American College of Medical Genetics for secondary analysis when using clinical sequencing used for diagnostic purposes. Our findings provide evidence that operationalizing patient choices beyond “all or none” is possible and when given the chance a subset of people will choose to learn some but not all results.

Lisa J. Martin, PhD

Simultaneous skin biome and keratinocyte genomic capture reveals microbiome differences by depth of sampling.

The skin is an essential organ, and failure of the skin barrier is a hallmark of atopic dermatitis. Skin tape stripping is a common non-invasive procedure used to collect keratinocytes and other resident skin cells. A challenge with prior tape stripping studies is that the nucleic acid yields were low, thus requiring the pooling of multiple tapes. This study uses dissolvable tape strips, originally designed for hydrographic applications, for simultaneous collection of the skin microbiome, keratinocyte epigenetics, and keratinocyte gene expression to characterize the surface biome and the underlying host skin response. These data demonstrate differences in gene expression and microbial ecology with each individual tape highlighting that the local environment is dependent on the depth of sampling; an observation missed by tape pooling. This novel non-invasive methodology will enhance our understanding of the omics of healthy and diseased skin.

Kathryn N. Weaver MD

A human importin-beta-related disorder: Syndromic thoracic aortic aneurysm caused by bi-allelic loss of function variants in IPO8

This paper defines a novel human syndrome caused by bi-allelic pathogenic variants in IPO8. Features of affected individuals overlap with those seen in individuals with Loeys-Dietz syndrome, and include thoracic aortic aneurysm, craniofacial anomalies, and skeletal differences. Evaluation of a mouse model (Ipo8-/-) revealed that mutant mice demonstrate progressive aortic dilation, with deterioration of elastic fibers in the ascending aorta on histology. Further, downregulated TGFB pathway inhibitors SMAD6 and SMAD7 in mutant aortas and pSMAD2 increased. The human and mouse phenotypes both support that loss of function of IPO8 leads to a Loeys-Dietz-like syndrome via dysregulated TGFB pathway signaling.