Towards precision medicine

Key Points

  • Precision medicine describes the definition of disease at a higher resolution by genomic and other technologies to enable more precise targeting of subgroups of disease with new therapies. Prominent examples include cystic fibrosis and cancer.

  • Clinical genomics exists at the intersection of sequencing-led discovery genetics in population cohorts and historical low-throughput approaches to genetic diagnosis in patients. As a result of the different aims of these two endeavours, technologies and algorithms that have been developed for discovery genomics need to be optimized before application to clinical medicine.

  • Areas of need include the improvement of sequencing technologies. Current short-read approaches are limited in areas of the genome of low complexity (such as repeats), regions of high GC content, regions that are highly polymorphic or that include small-scale (indel) or large-scale (structural variant) disruption of the open reading frame.

  • Possible routes to such improvements include long-read sequencing, improved algorithms for indel and structural variant calling, graph reference approaches and standardization of nomenclature.

  • One area that requires specific attention is the quality and coverage of sequence data for clinical genetic testing. In general, the emerging consensus standard is that the coding regions of interest (plus two base pairs on either side) should be covered by 20 high-quality (Q20) reads that are uniquely mapped.

  • To improve assertions of the disease causality of genetic variants, data sharing of both phenotypic and genotypic information across communities will be required. Projects such as ClinGen and its associated database ClinVar represent an important step in this direction. Large-scale population sequencing projects such as the UK Biobank and the US Precision Medicine Initiative Cohort Program will enhance our understanding of population-scale genetic variation in a way that optimizes our care of the individual with genetic disease.

Abstract

There is great potential for genome sequencing to enhance patient care through improved diagnostic sensitivity and more precise therapeutic targeting. To maximize this potential, genomics strategies that have been developed for genetic discovery — including DNA-sequencing technologies and analysis algorithms — need to be adapted to fit clinical needs. This will require the optimization of alignment algorithms, attention to quality-coverage metrics, tailored solutions for paralogous or low-complexity areas of the genome, and the adoption of consensus standards for variant calling and interpretation. Global sharing of this more accurate genotypic and phenotypic data will accelerate the determination of causality for novel genes or variants. Thus, a deeper understanding of disease will be realized that will allow its targeting with much greater therapeutic precision.

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Figure 1: The emergence of precision medicine.
Figure 2: Origins of reduced accuracy in clinical genomics from short sequencing reads.
Figure 3: Repeats, compound variants and nomenclature as challenges to accuracy in clinical genome sequencing.
Figure 4: Exomes, genomes and augmentation.
Figure 5: Quality-coverage metrics for the American College of Medical Genetics 56 most actionable genes.

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Acknowledgements

The author extends his grateful thanks to R. Goldfeder, A. Dainis, M. Grove, D. Church, M.J. Clark, S. Garcia, G. Chandratillake and C. Caleshu for helpful discussion and suggestions on the manuscript.

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Correspondence to Euan A. Ashley.

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E.A.A. is a co-founder of, and an advisor at, Personalis Inc.

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Glossary

Checkpoint receptors

Mediate important immune autoinhibitory pathways, including programmed cell death 1 (PD1) and cytotoxic T lymphocyte-associated protein 4 (CTLA4).

Pharmacogenomics

The study and application of the effect of genetic variation on the response to pharmaceuticals.

Black box warnings

Named for the black border surrounding the text of the warning on the package insert or label of a drug. They detail the safety concerns that are of a more serious nature than those described elsewhere on the package or label. The border is used when a serious adverse event can be caused by the medication or can be prevented by appropriate use of the medication.

Companion diagnostics

Diagnostic tests that help to direct the appropriateness of a specific drug therapy.

Linkage analysis

An approach to establish the probability that a given genomic region is associated with a phenotype, usually in an extended pedigree.

HapMap project

An international consortium aimed at characterizing the haplotype diversity of the human genome.

Shotgun

In shotgun sequencing, longer DNA fragments are broken into smaller fragments for sequencing using chain termination (Sanger) chemistry.

Pseudogenes

Copies of a gene that are no longer functional in the same way as the original gene, usually because of deactivating mutations, such as premature stop codons. Pseudogenes can be either processed (derived from retrotransposition of a mature transcript) or non-processed (derived from a DNA duplication event that includes a modification leading to a loss of transcription or translation).

Segmental duplications

Typically pericentromeric or subtelomeric duplications, concentrated in the Y chromosome, generally tens to hundreds of kilobases in length.

Short tandem repeats

Microsatellite DNA motifs consisting of 2–6 bp repeated elements of median length 25 bp and accounting for 1% of the genome. They predispose to DNA polymerase slippage events and high mutation rates. Recent work suggests an important role in gene expression.

Transposon-derived repeats

Repeats derived from transposons, which are DNA elements that can change their positions within the genome.

Paralogy

A paralogue is a gene related to another by duplication. In this Review, the words paralogy and paralogous are used as umbrella terms for areas of the human genome that are identical to each other. Note that paralogues can be formally distinguished from homologues (genes related to one another by descent from a common ancestor) and orthologues (genes related to one another by speciation).

De novo assembly

Arranging DNA sequence reads in the most likely order of origination without alignment to a reference sequence.

Structural variant

A region of DNA usually greater than 500 bases variant from a defined reference.

Lossy compression

A class of data encoding that reduces data size for storage, handling and transmission at the expense of loss of content.

Lossless compression

A class of data encoding where the original can be perfectly restored from the compressed file.

Compression heuristic

An approach to compression that is not designed to be optimal but is rather designed to be practical.

Variant call format

(VCF). A file format standard for the cataloguing of genetic variation in one or many genomes.

Major allele

The most common allele in a given population.

Mendelian disease

A genetic disease that follows traditionally recognized patterns of simple inheritance, for example, autosomal dominant.

Parsers

An algorithm with a specific application in translating one terminology to another.

ClinVar

A curated database of clinically relevant human genetic variation along with the evidence for its disease causality.

dbSNP

A minimally curated database of single nucleotide human genetic variation.

Splice dinucleotides

The almost invariant canonical dinucleotides that are crucial for splicing (GT: donor; AG: acceptor).

Univariate

Depending on only one variable.

Multivariate

Depending on multiple variables.

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Ashley, E. Towards precision medicine. Nat Rev Genet 17, 507–522 (2016). https://doi.org/10.1038/nrg.2016.86

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