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Human Genomics in Immunology

Robert L. Nussbaum, Jennifer M. Puck

The completion of the Human Genome Project in 2003, 50 years challenges to completing the human genome sequence are posed
after the landmark 1953 publication of the double-helical structure by regions that contain segmental duplications of nearly the same
of DNA by James Watson and Francis Crick, is correctly deemed sequence. 1
a major milestone in modern biology. The sequence provided
a first comprehensive and accurate view of the genetic makeup HUMAN VARIATION
of humans, with a low error rate and only a few hundred gaps
of indeterminate sequence. The first detailed picture of the The first publicly available human genome sequence was con-
structure of a composite human genome is for human genetics structed from a small number of individuals. Nonetheless, the
what Vesalius’s publication of a consensus structure of the human “reference” human genome sequence available at public websites
body, De humani corporis fabrica, was for anatomy. And, like is a consensus, composite haploid sequence and not the sequence
Vesalius’s work, it continues to serve as a foundation for further of any one individual. It is neither a “normal” genome nor a
scientific discovery in such areas as genetic variation, gene func- “control” genome; instead, it serves as a reference, providing
tion, human physiology, and the genetic basis for disease. The a universally available sequence against which the genomes of
years following the completion of the first human genome other individuals, as well as other species, can be compared and
sequencing have seen progress in all of these areas. any differences (“variants”) determined. Even before the original
human genome sequence was completed, the need to discover
KEY CONCEPTS as broad a range of human variations as possible in populations
from around the world was clearly recognized to be essential if
The sequence of the human genome and catalogue of extensive genome
variation among humans has revolutionized our approach to heritable we were to begin to understand how variations in the genome
immune disorders. lead to differences in phenotypic variations in traits and disease
Genomic variation between humans and other species illuminates susceptibilities. The first concerted efforts to catalogue human
conserved areas that are critical for normal function of gene genetic diversity after completion of the Human Genome Project
products. was the dbSNP (database of single nucleotide polymorphisms)
A variety of types of DNA variation are recognized, including single project, followed by the 1000 Genomes project. These initial
nucleotide changes, insertions or deletions of a few to many nucleo-
tides, copy number variants, and structural variants. catalogues that surveyed the extent of variation in both the
Interpretation of the significance of an observed variant in DNA sequence coding and the noncoding portions of the genome have been
may require consideration of its location, frequency in the population, supplemented enormously by more comprehensive sequencing
inheritance in a family, and specific effect on the resulting gene product. efforts, which produced the NHLBI GO Exome Sequencing
Project (ESP) and Exome Aggregation Consortium (EXaC).
These projects focus on variation within exomes of hundreds
GENOME ANNOTATION of thousands of individuals and have made a vast number of
variants and their frequency publicly available to researchers
A consensus sequence of the human genome is only the first and clinicians worldwide.
step in furthering our understanding of normal biological Variants can be classified as rare or common (polymorphic)
functions and how mutations lead to abnormal functions that according to their frequency in a population under study. Any
cause disease. The Human Genome Project has now matured variant present in >2% of the population (i.e., constituting >1%
into a number of important basic and applied research areas: (i) of the alleles at any locus in that population) is arbitrarily
acquiring a comprehensive catalogue of human variation and designated as polymorphic. With the advent of comprehensive
the impact of such variation on phenotype, including disorders DNA sequencing of larger and larger numbers of people from
of human development; (ii) comparing the genomes of humans across the globe, it has become clear that most variants (85%)
with those of other organisms, including model organisms and at any one base pair (bp) or segment of the genome have allele
human ancestors; and (iii) learning how to interpret all the frequencies substantially below the 1% cutoff for being a poly-
sequence elements within the genome, not just the codons. morphism and are, instead, considered rare, sometimes restricted
Even now, over a dozen years after “completion” of the human to a single ethnic group or even a single kindred. 2
genome sequence, a complete, accurate, and single contiguous DNA variation can also be classified according to the type of
stretch representing a reference human haploid genome is DNA change seen in the variant (Table 33.1). Single nucleotide
still being constructed, and updated versions of the genome variants (SNVs), insertion/deletion variants (indels), copy number
sequence continue to be released. As described below, the greatest variants (CNVs), and structural variants (SVs) can have different

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