Current Developments in Detection of Identity-by-Descent Methods and Applications

Identity-by-descent (IBD), the detection of shared segments inherited from a common ancestor, is a fundamental concept in genomics with broad applications in the characterization and analysis of genomes. While historically the concept of IBD was extensively utilized through linkage analyses and in studies of founder populations, applications of IBD-based methods subsided during the genome-wide association study era. This was primarily due to the computational expense of IBD detection, which becomes increasingly relevant as the field moves toward the analysis of biobank-scale datasets that encompass individuals from highly diverse backgrounds. To address these computational barriers, the past several years have seen new methodological advances enabling IBD detection for datasets in the hundreds of thousands to millions of individuals, enabling novel analyses at an unprecedented scale. Here, we describe the latest innovations in IBD detection and describe opportunities for the application of IBD-based methods across a broad range of questions in the field of genomics.

The Emerging Genetic Landscape of Hirschsprung Disease and Its Potential Clinical Applications

Hirschsprung disease (HSCR) is the leading cause of neonatal functional intestinal obstruction. It is a rare congenital disease with an incidence of one in 3,500–5,000 live births. HSCR is characterized by the absence of enteric ganglia in the distal colon, plausibly due to genetic defects perturbing the normal migration, proliferation, differentiation, and/or survival of the enteric neural crest cells as well as impaired interaction with the enteric progenitor cell niche. Early linkage analyses in Mendelian and syndromic forms of HSCR uncovered variants with large effects in major HSCR genes including RET, EDNRB, and their interacting partners in the same biological pathways. With the advances in genome-wide genotyping and next-generation sequencing technologies, there has been a remarkable progress in understanding of the genetic basis of HSCR in the past few years, with common and rare variants with small to moderate effects being uncovered. The discovery of new HSCR genes such as neuregulin and BACE2 as well as the deeper understanding of the roles and mechanisms of known HSCR genes provided solid evidence that many HSCR cases are in the form of complex polygenic/oligogenic disorder where rare variants act in the sensitized background of HSCR-associated common variants. This review summarizes the roadmap of genetic discoveries of HSCR from the earlier family-based linkage analyses to the recent population-based genome-wide analyses coupled with functional genomics, and how these discoveries facilitated our understanding of the genetic architecture of this complex disease and provide the foundation of clinical translation for precision and stratified medicine.

Structure of the exudate gum from Meryta sinclairii

A gum that exudes from the wounded trunk of the New Zealand native tree Meryta sinclairii has been isolated. The gum was completely precipitated by the β-glucosyl Yariv reagent and was thus determined to be an arabinogalactan-protein (AGP). It contained >95% w/w carbohydrate and only 2% w/w protein with a high level of hydroxyproline. SEC-MALLS showed that the gum had a weight-average molecular weight of 4.45×106Da compared with 6.02×105Da for gum arabic. Constituent sugar and linkage analyses were consistent with polymers comprised of a highly branched backbone of 1,3-linked galactopyranosyl (Galp) residues, with side-chains made up of arabinofuranose- (Araf) containing oligosaccharides, terminated variously by rhamnopyranosyl (Rhap), arabinopyranosyl (Arap), Galp and glucuronopyranosyl (GlcpA) residues. Analysis by one-dimensional and two-dimensional 1H and 13C NMR experiments confirmed the linkage analyses. The structure of the gum is discussed in comparison with the structure of gum arabic and other AGPs. © 2003 Elsevier Science Ltd. All rights reserved.

Structure of the exudate gum from Meryta sinclairii

A gum that exudes from the wounded trunk of the New Zealand native tree Meryta sinclairii has been isolated. The gum was completely precipitated by the β-glucosyl Yariv reagent and was thus determined to be an arabinogalactan-protein (AGP). It contained >95% w/w carbohydrate and only 2% w/w protein with a high level of hydroxyproline. SEC-MALLS showed that the gum had a weight-average molecular weight of 4.45×106Da compared with 6.02×105Da for gum arabic. Constituent sugar and linkage analyses were consistent with polymers comprised of a highly branched backbone of 1,3-linked galactopyranosyl (Galp) residues, with side-chains made up of arabinofuranose- (Araf) containing oligosaccharides, terminated variously by rhamnopyranosyl (Rhap), arabinopyranosyl (Arap), Galp and glucuronopyranosyl (GlcpA) residues. Analysis by one-dimensional and two-dimensional 1H and 13C NMR experiments confirmed the linkage analyses. The structure of the gum is discussed in comparison with the structure of gum arabic and other AGPs. © 2003 Elsevier Science Ltd. All rights reserved.

Haplotyping by linked-read sequencing (HLRS) of the genetic disease carriers for preimplantation genetic testing without a proband or relatives

Background: In order to mitigate the risk of allele dropout (ADO) and ensure the accuracy of preimplantation genetic testing for monogenic disease (PGT-M), it is necessary to construct parental haplotypes.. Typically, haplotype resolution is obtained by genotyping multiple polymorphic markers in both parents and a proband or a relative. Sometimes, single sperm typing, or tests on the polar bodies may also be useful. Nevertheless, this process is time-consuming. At present, there was no simple linkage analysis strategy for patients without affected relatives.Method: To solve this problem, we established a haplotyping by linked-read sequencing (HLRS) method without the requirement for additional relatives. First, the haplotype of the genetic disease carriers in the family was constructed by linked-read sequencing, and then the informative single nucleotide polymorphisms (SNPs) in upstream and downstream mutation region were selected to construct the embryo haplotype and to determine whether the embryo was carrying the mutation. Two families were selected to validate this method; one with alpha thalassemia and the other with NDP gene disorder.Results: The haplotyping by linked-read sequencing (HLRS) method was successfully applied to construct parental haplotypes without recruiting additional family members; the method was also validated for PGT-M. The mutation carriers in these families were sequenced by linked-read sequencing, and their haplotypes were successfully phased. Adjacent SNPs of the mutation gene were identified. The informative SNPs were chosen for linkage analyses to identify the carrier embryos. For the alpha thalassemia family, a normal blastocyst was transferred to the uterus and the accuracy of PGT-M was confirmed by amniocentesis at 16 weeks of gestation. Conclusions: Our results suggest that HLRS can be applied for PGT-M of monogenic disorders or de novo mutations where the mutations haplotype cannot be determined due to absence of affected relatives. Keywords: Preimplantation Genetic Testing for monogenic disease, Linked-read sequencing, Linkage analyses, Haplotype

Simulating hidden dynamics : Introducing Agent-Based Models as a tool for linkage analysis

Linkage analyses use data from panel surveys and content analyses to assess media effects under field conditions and are able to close the gap between experimental and survey-based media effects research. Results from current studies and simulations indicate, however, that these studies systematically under-estimate real media effects as they aggregate measurement errors and reduce the complexity of media content. In response to these issues, we propose a new method for linkage analysis which applies agent-based simulations to directly assess short-term media effects using empirical data as guideposts. Results from an example study modeling opinion dynamics in the run-up of a Swiss referendum show that this method outperforms traditional regression-based linkage analyses in detail and explanatory power. In spite of the time-consuming modeling and computation process, this approach is a promising tool to study individual media effects under field conditions.

Molecular Variants in Human Trace Amine-Associated Receptors and Their Implications in Mental and Metabolic Disorders

We provide a comprehensive review of the available evidence on the pathophysiological implications of genetic variants in the human trace amine-associated receptor (TAAR) superfamily. Genes coding for trace amine-associated receptors (taars) represent a multigene family of G-protein-coupled receptors, clustered to a small genomic region of 108 kb located in chromosome 6q23, which has been consistently identified by linkage analyses as a susceptibility locus for schizophrenia and affective disorders. Most TAARs are expressed in brain areas involved in emotions, reward and cognition. TAARs are activated by endogenous trace amines and thyronamines, and evidence for a modulatory action on other monaminergic systems has been reported. Therefore, linkage analyses were followed by fine mapping association studies in schizophrenia and affective disorders. However, none of these reports has received sufficient universal replication, so their status remains uncertain. Single nucleotide polymorphisms in taars have emerged as susceptibility loci from genome-wide association studies investigating migraine and brain development, but none of the detected variants reached the threshold for genome-wide significance. In the last decade, technological advances enabled single-gene or whole-exome sequencing, thus allowing the detection of rare genetic variants, which may have a greater impact on the risk of complex disorders. Using these approaches, several taars (especially taar1) variants have been detected in patients with mental and metabolic disorders, and in some cases, defective receptor function has been demonstrated in vitro. Finally, with the use of transcriptomic and peptidomic techniques, dysregulations of TAARs (especially TAAR6) have been identified in brain disorders characterized by cognitive impairment.

Simulating Hidden Dynamics. Introducing Agent-Based Models as a tool for linkage analysis

Linkage analyses use data from panel surveys and content analyses to assess media effects under field conditions and are able to close the gap between experimental and survey-based media effects research. Results from current studies and simulations indicate, however, that these studies systematically under-estimate real media effects as they aggregate measurement errors and reduce the complexity of media content. In response to these issues, we propose a new method for linkage analysis which applies agent-based simulations to directly assess short-term media effects using empirical data as guideposts.Results from an example study modeling opinion dynamics in the run-up of a Swiss referendum show that this method outperforms traditional regression-based linkage analyses in detail and explanatory power. In spite of the time-consuming modeling and computation process, this approach is a promising tool to study individual media effects under field conditions.