Structural variation in human genomics: 6 things to read right now

The significance of structural variation in human genomics is becoming increasingly established in many fields, from cancer to neurology and the mechanisms of rare disease. With research moving at an unprecedented pace, we’ve picked out our 6 top reads that cover both the fundamentals of structural variation detection and the latest in published work using nanopore sequencing.

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  1. REVIEW: Genetic Variation, Comparative Genomics, and the Diagnosis of Disease.

Human genetic variation is the core concept underlying the majority of genomics research into health, disease, evolution and many other aspects of existence. However, structural variation, as opposed to single nucleotide or small variation, has only relatively recently been recognised as a substantial contributor to phenotype. For the ultimate primer in understanding how SVs relate to other classes of genetic variation, Evan Eichler’s review delves into both historical and future-looking perspectives on the field - as well as handy glossary information on all the terminology you need.

Read the full article | 30 min read

Listen to the interview with the author | 8 min listen

  1. PUBLICATION: Long read sequencing of 1,817 Icelanders provides insight into the role of structural variants in human disease

Genome-wide understanding of how structural variation affects populations will be fundamental to the future of healthcare and scientific research. Doruk Beyter et al note that long-read sequencing will serve to improve this understanding, and tackle the largest project of this scale to date involving 1,817 Icelanders. With this approach, the team found ~ 23,000 SVs per individual, approximately five times the number found with short read sequencing, as well as correlating rarer SVs with a larger size.

Read the full paper | 30 min read

  1. BLOG: Resolving structural variants causing antithrombin deficiency

Antithrombin deficiency is the most severe form of thrombophilia, a condition which significantly increases risk of blood clots, and despite its first description 55 years ago and the subsequent identification of over 440 causative variants, 30% of cases still remain unresolved. This blog summarises Alba Sanchis-Juan and team’s work to establish a native long-read approach to resolving the molecular basis of cases with unknown genetic defects, to investigate both structural variation and epigenetic regulatory changes in future projects.

Read the full blog | 10 min read

  1. PUBLICATION: Cas9-based enrichment and single-molecule sequencing for precise characterization of genomic duplications

Copy number changes of single genes can be incidentally detected in patients who are given a genome-wide diagnostic screen, but the potential pathogenicity of these changes can be hard to determine given the variable length and structure of the variation. To allow for clinical management, incidental findings require validation, including length estimation and breakpoint determination. For this purpose, Chris Watson and team employed a Cas9-based selection strategy for the regions of interest determined by the whole-genome screen, which then went on to be sequenced, and the information used to develop breakpoint determination assays suitable for familial screening for carriers.

Read the full paper | 30 min read

  1. POSTER: Resolving highly complex rearrangements of genomic architecture using long PromethION reads

Complex structural variants can span over an extremely large genomic range, and can represent severe phenotypic consequences. An example of this is a duplication-inverted triplication-duplication event displayed in certain patients with Temple syndrome, covering over 2 Mb of sequence and leading into absence of heterozygosity. This poster explores the ability of long nanopore sequencing reads to resolve the precise structure of this event, as well as detecting the lack of a hypermethylated allele, indicating loss of imprinting.

Read the full poster: 5 min read

  1. WHITE PAPER: Advantages of long reads for structural variation analysis

To date, the majority of human genetic research has focused on single nucleotide variations, but it is now known that structural variation accounts for more than 10-fold the amount of variable bases than SNVs. Much of existing research relies on short-read sequencing technologies, which present significant challenges when it comes to mapping and identifying large-scale changes, and so the advent of accessible long-read sequencing has really accelerated research in this field. In this white paper, case studies are examined on the role nanopore sequencing has played in association of structural variation to genomic diversity and disease, and the role it might continue to play in the future.

Read the full white paper | 60 min read

Want to know more about calling structural variation from nanopore data? You can find out more about the practicalities in our guide “Getting started with structural variation detection”.

Download guide.