Integration of Hi-C with short and long-read genome sequencing reveals the structure of germline rearranged genomes

Here the authors characterize structural variations (SVs) in a cohort of individuals with complex genomic rearrangements, identifying breakpoints by employing short- and long-read genome sequencing and investigate their impact on gene expression and the three-dimensional chromatin architecture. They find breakpoints are enriched in inactive regions and can result in chromatin domain fusions.Structural variants are a common cause of disease and contribute to a large extent to inter-individual variability, but their detection and interpretation remain a challenge. Here, we investigate 11 individuals with complex genomic rearrangements including germline chromothripsis by combining short- and long-read genome sequencing (GS) with Hi-C. Large-scale genomic rearrangements are identified in Hi-C interaction maps, allowing for an independent assessment of breakpoint calls derived from the GS methods, resulting in >300 genomic junctions. Based on a comprehensive breakpoint detection and Hi-C, we achieve a reconstruction of whole rearranged chromosomes. Integrating information on the three-dimensional organization of chromatin, we observe that breakpoints occur more frequently than expected in lamina-associated domains (LADs) and that a majority reshuffle topologically associating domains (TADs). By applying phased RNA-seq, we observe an enrichment of genes showing allelic imbalanced expression (AIG) within 100 kb around the breakpoints. Interestingly, the AIGs hit by a breakpoint (19/22) display both up- and downregulation, thereby suggesting different mechanisms at play, such as gene disruption and rearrangements of regulatory information. However, the majority of interpretable genes located 200 kb around a breakpoint do not show significant expression changes. Thus, there is an overall robustness in the genome towards large-scale chromosome rearrangements

Integration of Hi-C with short and long-read genome sequencing reveals the structure of germline rearranged genomes

Structural variants are a common cause of disease and contribute to a large extent to inter-individual variability, but their detection and interpretation remain a challenge. Here, we investigate 11 individuals with complex genomic rearrangements including germline chromothripsis by combining short- and long-read genome sequencing (GS) with Hi-C. Large-scale genomic rearrangements are identified in Hi-C interaction maps, allowing for an independent assessment of breakpoint calls derived from the GS methods, resulting in >300 genomic junctions. Based on a comprehensive breakpoint detection and Hi-C, we achieve a reconstruction of whole rearranged chromosomes. Integrating information on the three-dimensional organization of chromatin, we observe that breakpoints occur more frequently than expected in lamina-associated domains (LADs) and that a majority reshuffle topologically associating domains (TADs). By applying phased RNA-seq, we observe an enrichment of genes showing allelic imbalanced expression (AIG) within 100 kb around the breakpoints. Interestingly, the AIGs hit by a breakpoint (19/22) display both up- and downregulation, thereby suggesting different mechanisms at play, such as gene disruption and rearrangements of regulatory information. However, the majority of interpretable genes located 200 kb around a breakpoint do not show significant expression changes. Thus, there is an overall robustness in the genome towards large-scale chromosome rearrangements

De novo unbalanced translocations have a complex history/aetiology

We investigated 52 cases of de novo unbalanced translocations, consisting in a terminally deleted or inverted-duplicated deleted (inv-dup del) 46th chromosome to which the distal portion of another chromosome or its opposite end was transposed. Array CGH, whole-genome sequencing, qPCR, FISH, and trio genotyping were applied. A biparental origin of the deletion and duplication was detected in 6 cases, whereas in 46, both imbalances have the same parental origin. Moreover, the duplicated region was of maternal origin in more than half of the cases, with 25% of them showing two maternal and one paternal haplotype. In all these cases, maternal age was increased. These findings indicate that the primary driver for the occurrence of the de novo unbalanced translocations is a maternal meiotic non-disjunction, followed by partial trisomy rescue of the supernumerary chromosome present in the trisomic zygote. In contrast, asymmetric breakage of a dicentric chromosome, originated either at the meiosis or postzygotically, in which the two resulting chromosomes, one being deleted and the other one inv-dup del, are repaired by telomere capture, appears at the basis of all inv-dup del translocations. Notably, this mechanism also fits with the origin of some simple translocations in which the duplicated region was of paternal origin. In all cases, the signature at the translocation junctions was that of non-homologous end joining (NHEJ) rather than non-allelic homologous recombination (NAHR). Our data imply that there is no risk of recurrence in the following pregnancies for any of the de novo unbalanced translocations we discuss here

Transactions Papers On the Performance of High-Rate TPC/SPC Codes and LDPC Codes Over Partial Response Channels

Abstract—This paper evaluates two-dimensional turbo product codes based on single-parity check codes (TPC/SPC) and low-density parity check (LDPC) codes for use in digital magnetic recording systems. It is first shown that the combination of a TPC/SPC code and a precoded partial response (PR) channel results in a good distance spectrum due to the interleaving gain. Then, density evolution is used to compute the thresholds for TPC/SPC codes and LDPC codes over PR channels. Analysis shows that TPC/SPC codes have a performance close to that of LDPC codes for large codeword lengths. Simulation results for practical block lengths show that TPC/SPC codes perform as well as LDPC codes in terms of bit error rate, but possess better burst error statistics which is important in the presence of an outer Reed–Solomon code. Further, the encoding complexity of TPC/SPC codes is only linear in the codeword length and the generator matrix does not have to be stored explicitly. Based on the results in the paper and these advantages, TPC/SPC codes seem like a viable alternative to LDPC codes. Index Terms—Data storage system, density evolution, iterative decoding, low-density parity check codes, message-passing decoding, partial response channels, precoding, turbo product codes. I

Iterative Decoding of Turbo Product Codes over PR-equalized Lorentzian Channels with Colored Noise

Abstract — Following the trend of turbo codes and low density parity check (LDPC) codes, single-parity turbo product codes (TPC/SPC) are being seriously considered for application in future high-density recording systems. Recent work on TPC/SPC codes has focused on ideal partial response channels with additive white Gaussian noise. This work extends the investigation to a more realistic equalized Lorentzian channel model where imperfect channel shaping, colored noise and recording density effect are taken into consideration. The effect of precoding is discussed and the interleaving gain is quantified. Simulation results of the turbo decoding system with both channel models are presented. A comprehensive evaluation is conducted, including BER performance, code rate selection, equalization targets and error statistics, which demonstrate TPC/SPC codes to be a promising candidate for future high-density recording systems. I

Georghiades, “Thresholds for iterative equalization of partial response channels using density evolution

This paper focuses on the computing of the thresholds for iterative equalization and decoding of partial response channel, such as what are of interest in high density magnetic recording. Extensive simulations on the performance of turbo codes, low density parity check (LDPC) codes and single-parity check turbo product codes (TPC/SPC) over partial response channels reveal very encouraging bit error rate (BER) performance, but cast little insight into the fundamental limitation within the existing suboptimal decoding. This work uses the method of density evolution with Gaussian approximation to investigate the achievable capacity by taking into consideration of both the code’s structural properties and the iterative decoding algorithm. A unified framework involving different outer codes, including (punctured) convolutional codes (also known as serial turbo), LDPC codes and TPC/SPC codes, is presented. Certain interesting issues in the decoding optimization are investigated. The tightness demonstrated by the bound attributes density evolution to be a very useful tool to be extended for capacity analysis of a broad range of iterative processes

Georghiades, “On the performance of turbo product codes and LDPC codes over partial response channels

Abstract—This paper evaluates the performance of single-parity check turbo product codes (TPC/SPC) over partial response channels. A rate-0.94 and a rate-0.89 TPC/SPC code are considered for use with PR4/EPR4 channels with proper precoding and with turbo equalization. Gains of 4.5 to 5 dB are obtained at BER of 10 S, revealing performance comparable to that of low density parity check codes. Apart from its linear encoding/decoding complexity and highly parallelizable decoding algorithm, TPC/SPC codes demonstrate favorable error statistics which are in harmony with the outer Reed–Solomon error correction code (RS-ECC), indicating it to be a promising candidate for future recording systems. Index Terms—Data storage system, iterative decoding, message-passing decoding, partial response channels, precoding, turbo product codes. I