TAIPEI, TAIWAN, Aug. 31, 2021 - GRCh38 was first introduced as the official standard human reference genome in 2013, but many research facilities have not made the switch. Perhaps you’re part of that group, or maybe you’ve never encountered the term “human reference genome” before. Regardless of which, we hope that this will serve as a comprehensive guide into what human reference genomes are, what they are used for and hopefully shed light on which reference build best suits your needs.
What is the Human Reference Genome?
The human reference genome is a DNA blueprint that is essential for clinical, research, and forensic use and can serve to predict novel genes based on available data. The human reference genome is the consensus of individual genomes, and is deemed as the standard for most applications within the field of genomic research. In short, it is an “idea” of what a typical, normal human genome should look like. It is created by using the combined technology and research of global partners in order to provide a basis on which research and treatment can be conducted.
The Role of the Genome Reference Consortium
After the human genome project was completed in 2003, the International Genome Reference Consortium (GRC) was formed. The assembly and sequence of the human reference genome is maintained by the GRC. The primary objective of the GRC, in the case of humans, is to provide the best and most accurate human genome reference up to date as possible. Choosing the right human reference is pivotal because it can impact the ability to identify variations that are meaningful in a genome sequence; to identify between what is healthy versus what may be pathological.
Is there a Perfect Genome Reference Build? Three improvements made on the latest reference genome
The latest build of the human genome reference is the GRCh38 (for Genome Research Consortium human build 38, or alternatively, hg38), with its preceding version to be the GRCh37 (hg19). There have been three main updates in this build that make it superior to its predecessor. These improvements are as follows: a rectification for incorrect reads, an inclusion of model centromere sequences, and an addition of alternate loci. In addition, this build continues to be updated to this day with new alternate scaffolds and patches. However, perfection is not at all an easy feat. Ideally, a reference build should encompass all the possible genetic information of a human and be capable of detecting all mutations for those genes. It is unlikely any build will ever truly achieve this, but with newer builds and updates, the potential to come closer to that goal becomes greater.
Why the reluctance to make the switch? GRCh37 vs GRCh38
Although it may seem logical for clinical labs to make the switch from the GRCh37 to the GRCh38 reference genome, it seems that most clinical labs are reluctant to implement the change. According to a study by the American Journal of Human Genetics conducted by Li and Dawood , GRCh37 remains to be more widely used amongst clinical laboratories. The primary reason behind this reluctance appears to be based on reliance. GRCh37 was released in 2009 and was held as the standard in the field and was used in many foundational research projects. It by no means was a bad build and it has had a crucial role in the field of genomics. When Li and Dawood compared the two builds in laboratory testing, they found that there are areas in which GRCh37 outperforms the new build in detecting some mendelian variants. However, the new build is readily being updated and worked on to try to overcome those challenges. Overall, both builds have positive elements that are worthy of consideration depending on the uses that one needs those reference builds for.
Financial Constraints- is the investment worth it?
There are two other reasons that may inhibit users from making the switch to GRCh38, the first of which is time constraints, followed by its financial constraints. There was a survey conducted recently by The Journal of Molecular Diagnostics  in which they analyzed both how many laboratories have made the switch and if they have not, why they have not. Their results showed that only 7% of the laboratories they surveyed had made the switch to build GRCh38 and of those that did not, 54% had no intention of making the switch. The primary reason that was identified as having led to that decision was due to the cost outweighing the benefit of switching builds. Making the switch is a financial investment that requires powerful computers and staff to conduct the change.
Time Constraints- time is of the essence, but it may not be affordable
The second concern comes from having to re-analyse the GRCh38 reference genome as more time and effort would be required to be invested than would outweigh the fact that the current build is performing well enough. Secondary analysis is the stage of genomic sequencing with the highest amount of throughput. Many laboratories are concerned about the times and costs associated with that reanalyse process.
How Acceleration Solutions Can Help- WASAI Lightning tackles both financial and timely concerns!
Despite these challenges, there have been many pivotal advancements in secondary analysis acceleration. The WASAI Lightning Family for example, are solutions which can mitigate this very problem of a major cost-performance concern. It matches its high throughput rates to that of a HPC, but without the “high” costs- all while maintaining accuracy and “lightning” speed. For us here at WASAI, reference genomes are a topic of particular interest because they are an integral component of secondary analysis, and WASAI Lightning specializes in the acceleration of secondary analysis. The field of genomics is in many ways a collaborative one. Advancements that are made in one area of the field are pivotal for others.
Switching reference builds is a tough decision, but it also may be the right decision for many laboratories. Reference builds as a whole have such an important place in both genetic research and the development of new precision treatments. As a field, genomics is constantly evolving and new builds aid in the enhancement of our understanding about the human genome. With the inclusion of more and more sections, variants of the human genome can be detected. As a company, our goal in this field is to develop acceleration solutions as an informatics specialist. Acceleration solutions have the potential to alleviate the concerns that many laboratories face when considering switching reference builds. GRCh38 brings with it many useful updates and patches to make it more useful for variant calling. As the current build, it is likely only to continue to be refined, and may be the right choice for many laboratories.
 Exome variant discrepancies due to reference-genome differences, Li, He et al., The American Journal of Human Genetics, Volume 108, Issue 7, 1239 - 1250
 Factors Affecting Migration to GRCh38 in Laboratories Performing Clinical Next-Generation Sequencing, Lansdon, Lisa A. et al., The Journal of Molecular Diagnostics, Volume 23, Issue 5, 651 - 657
About WASAI Technology Inc.
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