Development and Role of the Human Reference Sequence in Personal Genomics


Genome maps, like geographical maps, need to be interpreted carefully. Although maps are essential to exploration and navigation they cannot be completely accurate. Humans have been mapping the world for several millennia, but genomes have been mapped and explored for just a single century with the greatest advancements in making a sequence reference map of the human genome possible in the past 30 years. After the deoxyribonucleic acid (DNA) sequence of the human genome was completed in 2003, the reference sequence underwent several improvements and today provides the underlying comparative resource for a multitude genetic assays and biochemical measurements. However, the ability to simplify genetic analysis through a single comprehensive map remains an elusive goal.

Key Concepts:

  • Maps are incomplete and contain errors.

  • DNA sequence data are interpreted through biochemical experiments or comparisons to other DNA sequences.

  • A reference genome sequence is a map that provides the essential coordinate system for annotating the functional regions of the genome and comparing differences between individuals' genomes.

  • The reference genome sequence is always product of understanding at a set point in time and continues to evolve.

  • DNA sequences evolve through duplication and mutation and, as a result, contain many repeated sequences of different sizes, which complicates data analysis.

  • DNA sequence variation happens on large and small scales with respect to the lengths of the DNA differences to include single base changes, insertions, deletions, duplications and rearrangements.

  • DNA sequences within the human population undergo continual change and vary highly between individuals.

  • The current reference genome sequence is a collection of sequences, an assembly, that include sequences assembled into chromosomes, sequences that are part of structurally complex regions that cannot be assembled, patches (fixes) that cannot be included in the primary sequence, and high variability sequences that are organised into alternate loci.

  • Genetic analysis is error prone and the data require validation because the methods for collecting DNA sequences create artifacts and the reference sequence used for comparative analyses is incomplete.

Keywords: DNA sequencing; human genome; genomics; reference sequence; reference assembly; next generation sequencing; massively parallel

Figure 1.

Genomics Genealogy. Genomic mapping evolved from defining genomic distances as statistical values to base positions through a series of advancements over a 70‐year period. Modern DNA sequencing provided high‐resolution maps that cannot be utilised in a multitude of NGS based experiments. In one branch, new reference genomes continue to be developed through de novo DNA sequencing. In this branch DNA and RNA can also be isolated from different environments to sample the genes and organisms that may be present. The other two branches rely on a reference sequence to compare sequence differences between individuals or cells within tissues (Variation Assays), or measure genetic controls and biochemical processes (Functional Genomics) with the ultimate goal of linking genotype to phenotype in highly detailed ways. Numerous variation and functional genomics assays have been described (Mason et al., ; Shendure and Lieberman Aiden, ).



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Further Reading

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Shreeve J (2007) The Genome War : How Craig Venter Tried to Capture the Code of Life and Save the World. New York, NY: Random House Digital, Inc.

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Smith, Todd M, and Porter, Sandra G(Jun 2014) Development and Role of the Human Reference Sequence in Personal Genomics. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0025334]