The dynamic three-dimensional (3D) organization of the human genome (the 4D nucleome) is linked to genome function. Here we describe efforts by the 4D Nucleome Project ¹ to map and analyse the 4D nucleome in widely used H1 human embryonic stem cells and immortalized fibroblasts (HFFc6). We produced and integrated diverse genomic datasets of the 4D nucleome, each contributing unique observations, which enabled us to assemble extensive catalogues of more than 140,000 looping interactions per cell type, to generate detailed classifications and annotations of chromosomal domain types and their subnuclear positions, and to obtain single-cell 3D models of the nuclear environment of all genes including their long-range interactions with distal elements. Through extensive benchmarking, we describe the unique strengths of different genomic assays for studying the 4D nucleome, providing guidelines for future studies. Three-dimensional models of population-based and individual cell-to-cell variation in genome structure showed connections between chromosome folding, nuclear organization, chromatin looping, gene transcription and DNA replication. Finally, we demonstrate the use of computational methods to predict genome folding from DNA sequence, which will facilitate the discovery of potential effects of genetic variants, including variants associated with disease, on genome structure and function.

New genome pipeline enables seamless execution of processing, analyzing, and visualizing of ChIA-PET data.

We analyze the performance of TCP and TCP with network coding (TCP/NC) in lossy wireless networks. We build upon the simple framework introduced by Padhye et al. and characterize the throughput behavior of classical TCP as well as TCP/NC as a function of erasure rate, round-trip time, maximum window size, and duration of the connection. Our analytical results show that network coding masks erasures and losses from TCP, thus preventing TCP's performance degradation in lossy networks, such as wireless networks. It is further seen that TCP/NC has significant throughput gains over TCP. In addition, we simulate TCP and TCP/NC to verify our analysis of the average throughput and the window evolution. Our analysis and simulation results show very close concordance and support that TCP/NC is robust against erasures. TCP/NC is not only able to increase its window size faster but also to maintain a large window size despite losses within the network, whereas TCP experiences window closing essentially because losses are mistakenly attributed to congestion.Comment: 9 pages, 12 figures, 1 table, submitted to IEEE INFOCOM 201

We propose a secure scheme for wireless network coding, called the algebraic watchdog. By enabling nodes to detect malicious behaviors probabilistically and use overheard messages to police their downstream neighbors locally, the algebraic watchdog delivers a secure global self-checking network. Unlike traditional Byzantine detection protocols which are receiver-based, this protocol gives the senders an active role in checking the node downstream. The key idea is inspired by Marti et al.'s watchdog-pathrater, which attempts to detect and mitigate the effects of routing misbehavior. We first focus on a two-hop network. We present a graphical model to understand the inference process nodes execute to police their downstream neighbors; as well as to compute, analyze, and approximate the probabilities of misdetection and false detection. We also present an algebraic analysis of the performance using an hypothesis testing framework that provides exact formulae for probabilities of false detection and misdetection. We then extend the algebraic watchdog to a more general network setting, and propose a protocol in which we can establish trust in coded systems in a distributed manner. We develop a graphical model to detect the presence of an adversarial node downstream within a general multi-hop network. The structure of the graphical model (a trellis) lends itself to well-known algorithms (e.g. the Viterbi algorithm) which can compute the probabilities of misdetection and false detection. We show that as long as the min-cut is not dominated by the adversaries, upstream nodes can monitor downstream neighbors and allow reliable communication with certain probability. Finally, we present simulation results that support our analysis.

The dynamic three-dimensional (3D) organization of the human genome (the “4D Nucleome”) is closely linked to genome function. Here, we integrate a wide variety of genomic data generated by the 4D Nucleome Project to provide a detailed view of human 3D genome organization in widely used embryonic stem cells (H1-hESCs) and immortalized fibroblasts (HFFc6). We provide extensive benchmarking of 3D genome mapping assays and integrate these diverse datasets to annotate spatial genomic features across scales. The data reveal a rich complexity of chromatin domains and their sub-nuclear positions, and over one hundred thousand structural loops and promoter-enhancer interactions. We developed 3D models of population-based and individual cell-to-cell variation in genome structure, establishing connections between chromosome folding, nuclear organization, chromatin looping, gene transcription, and DNA replication. We demonstrate the use of computational methods to predict genome folding from DNA sequence, uncovering potential effects of genetic variants on genome structure and function. Together, this comprehensive analysis contributes insights into human genome organization and enhances our understanding of connections between the regulation of genome function and 3D genome organization in general.

Chromatin topology can impact gene regulation, but how evolutionary divergence in chromatin topology has shaped gene regulatory landscapes for distinctive human traits remains poorly understood. CTCF sites determine chromatin topology by forming domains and loops. Here, we show evolutionary divergence in CTCF-mediated chromatin topology at the domain and loop scales during primate evolution, elucidating distinct mechanisms for shaping regulatory landscapes. Human-specific divergent domains lead to a broad rewiring of transcriptional landscapes. Divergent CTCF loops concord with species-specific enhancer activity, influencing enhancer connectivity to target genes in a concordant yet constrained manner. Under this concordant mechanism, we establish the role of human-specific CTCF loops in shaping transcriptional isoform diversity, with functional implications for disease susceptibility. Furthermore, we validate the function of these human-specific CTCF loops using human forebrain organoids. This study advances our understanding of genetic evolution from the perspective of genome architecture.