Download Emanuel BS, Warren ST , Garber KB. The human genome: a diamond in the rough. Curr Opin Genet Dev. 2012 Jun;22(3):189-90. doi: 10.1016/j.gde.2012.04.005. Epub 2012 May 18. No abstract available.

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The human genome: a diamond in the rough
Editorial overview
Beverly S Emanuel, Stephen T Warren and Kathryn B Garber
Current Opinion in Genetics & Development
2012, 22:189–190
For a complete overview see the Issue
Available online 18th May 2012
0959-437X/$ – see front matter, # 2012
Elsevier Ltd. All rights reserved.
DOI http://dx.doi.org/10.1016/j.gde.2012.04.005
Beverly S Emanuel
Department of Pediatrics, Perelman School
of Medicine at the University of Pennsylvania,
3615 Civic Center Blvd., Philadelphia, PA
19104, USA
e-mail: [email protected]
Beverly S. Emanuel is the Chief, Division of
Human Genetics and Molecular Biology and
the Charles E. Upham Professor of Pediatrics
at the Perelman School of Medicine at the
University of Pennsylvania. She is a human
geneticist investigating several diseases
caused by abnormalities of human
chromosomes, particularly chromosome 22.
Stephen T Warren and Kathryn
B Garber
Department of Human Genetics, Emory
University School of Medicine, 615 Michael
Street, Atlanta, GA 30322, USA
e-mail: [email protected]
Stephen T. Warren is the William Patterson
Timmie Professor and Charles Howard
Candler Chair of Human Genetics as well as
Professor of Biochemistry and of Pediatrics
at Emory University. Dr. Warren is the past
President of the American Society of Human
Genetics and former Editor-in-Chief of The
American Journal of Human Genetics. He is a
member of the Institute of Medicine and the
National Academy of Sciences.
Kathryn B. Garber is an Assistant Professor
of Human Genetics at Emory University
School of Medicine. She develops and
implements genetics education programs for
medical and allied health students, as well as
for graduate students and fellows
specializing in human genetics. She is a past
Deputy Editor and current Features Editor for
The American Journal of Human Genetics.
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In just over ten years, we have moved from a rough draft to a much more
complete picture of the human genome. One could argue, though, that we still
only have a rough understanding of how to interpret a full genome sequence
and that we need to move from an understanding of individual genes towards
an understanding of genomes. A major advance that the Human Genome
Project has engendered is the capacity to complete whole genome or whole
exome sequencing within a reasonable amount of time and for a reasonable
cost, which has drawn much attention over the past two years. The ultimate
goal is to connect accurately an individual’s genetic variation with their
eventual health outcomes. To date, exciting successes have been achieved
in matching clear gene mutations with rare phenotypes. However, even in this
seemingly simple type of situation, success is frequently elusive. There are
several steps to this process: detecting the full complement of genetic
variation while weeding out false positive sequence results, ascribing meaning
to this variation in terms of gene or protein expression, and interpreting its
effect on an individual’s health. In order to maximize the utility of genetic
information, we need to have a greater understanding of each of these steps.
Each of these facets of genetic variation is a topic for exploration in this issue of
Current Topics in Genetics and Development, in which we explore the molecular
and genetic bases of disease, hoping to see clearly this diamond in the rough.
We begin with a discussion of the ways in which mutation occurs in the first
place. This set of four reviews describes mechanisms by which specific types
of genetic variation arise. L1 retrotransposons can generate variation in two
ways, as described by Dustin Hancks and Haig Kazazian. For one, L1s can
insert copies of their own RNA, as well as that of other RNAs, to new locations
in the genome. Once inserted, these repeated elements in the genome serve as
substrates for non-allelic homologous recombination, leading to deletions and
duplications. Retrotransposition was originally thought to take place in the
germline, and therefore were considered to have consequence only between
generations. Newer data suggest the events actually occur somatically the
majority of the time, causing us to re-think the implications of these insertions,
including how often and in what circumstances these somatic insertions cause
cancer and what might be their impact in the brain.
Extensive sequence analysis across the breakpoints of genomic rearrangements has allowed us to contrast the origins of different classes of rearrangements. As described in two reviews, one by Tom Glover and colleagues and
the other by Jim Lupski and colleagues, recurrent rearrangements occur
meiotically, whereas nonrecurrent copy number variation and complex
rearrangements occur mitotically. Several factors govern the likelihood
and resulting products of non-allelic homologous recombination, such as
the length and orientation of the flanking repeats and the presence of
Current Opinion in Genetics & Development 2012, 22:189–190
190 Molecular and genetic bases of disease
recombination hotspot motifs. Nonrecurrent copy number
variation, on the contrary, is induced through replication
stress and is biased towards de novo variation arising paternally, owing to differences in male and female gamete
generation. There are many breakpoints to sequence when
it comes to the newly discovered process of chromosome
shattering called chromothripsis. Even so, we do have some
initial information on the contributory mechanisms.
Sequence analysis of breakpoints has also furthered our
understanding of certain recurrent translocations, including t(11;22). As reviewed by Beverly Emanuel and
colleagues, the breakpoint on each of the participating
chromosomes occurs in the center of a palindromic
sequence spanning several hundred base pairs. These
sequences form secondary structure that leads to genomic
instability and translocation, the likelihood of which is
influenced by polymorphism in the palindromic repeats.
The next facet of human genetics that is explored in this
issue is the architecture of particular genetic diseases. As
we move from the era dominated by genome-wide association studies and the discovery of copy number variation
and into a realm where we can identify rare sequence
variation, each technology has yielded genetic variation
that contributes to autism and schizophrenia, as summarized by Bernie Devlin and Steve Scherer and by Jennifer
Mulle. As we add each piece to this puzzle, we have
gained insight into the pathways that influence the development of these disorders, which in turn gives us
targets for drug intervention. At this point, known genetic
aetiologies for either disease range from rare, de novo
sequence changes of strong effect to structural variation
and to combinations of common risk alleles. The fact that
an etiology is not uncovered in a significant fraction of
patients argues there is much yet to be found.
Genome sequencing technologies have also increased our
understanding of the development and progression of
cancer, as reviewed by Elaine Mardis. For certain cancers,
this already allows us to better predict prognosis and has,
in some cases, allowed the selection of targeted therapies.
Once the underlying cause of a genetic disease is uncovered, the next step is to unravel the mechanism by which
this change led to disease. This is the subject of two
reviews, one by Harry Orr on the polyglutamine disorders
and one by Steve Warren and colleagues on the Fragile X
syndrome. Although both types of disorders are caused by
the expansion of specific repetitive sequences in the genome, they cause disease in very different ways. Orr
describes the compilation of data suggesting that neurodegeneration induced by polyglutamine expansions is tied
to an enhancement of the native function of the host
protein that contains the glutamine tract. The repeat
expansions that cause Fragile X syndrome, on the contrary,
lead to a loss of function owing to gene silencing. Loss of
Current Opinion in Genetics & Development 2012, 22:189–190
this RNA-binding protein, which regulates protein translation at the synapse, impairs normal synaptic plasticity.
Experiments in induced pluripotent stem cells and human
embryonic stem cells are helping us to understand the
mechanism by which repeat expansion silences this gene.
Although the first three segments of this issue describe how
far we have come in our understanding of genetic disease,
the last segment highlights the frontiers in our understanding of these diseases. In the realm of technology, Lisa
Shaffer, Roger Schultz, and Blake Ballif describe a twist on
comparative genomic hybridization, called translocation
comparative genomic hybridization, through which
balanced translocations can be detected. The technique
involves linear amplification of DNA, followed by hybridization to a comparative genome hybridization array that
targets genomic regions involved in leukemia or lymphoma. Discriminating the underlying genetic cause of
these blood disorders can better define the disease and
provide information for prognosis and treatment decisions.
From a completely different technology angle, George
Daley and colleagues compare different states of pluripotency and what is known about these states in animal
models and in humans. A more complete understanding
of these states is needed so that we can determine how to
best induce pluripotency in humans for use in therapies.
Moving on to the implications of genetic variation, Florian
Pauler et al. describe a new type of unspliced, long noncoding RNA, called macro non-coding RNAs, that are
believed to regulate gene expression. They discuss mechanisms by which these RNAs might act. And finally, Erica
Davis and Nicholas Katsanis discuss ciliopathies through a
systems biology lens. They highlight the fact that, even
though these are typically classified as Mendelian diseases,
variation in genes for other ciliary components can influence patient phenotype. Hopefully, studying the genetic
underpinnings of the ciliopathies will help us to understand how genetic variation at multiple sites combines with
a ‘causative’ mutation to yield the ultimate phenotypic
outcome.
This last idea highlights the challenge that is faced as one
moves from studies of rare Mendelian traits to exploration
of the combined genetic contributions to common phenotypes. This will require an additional step in the process of
interpreting genetic variation: that is, interpreting genetic
variation within the totality of the genomic variation.
From the development of technologies that helped us
discover new types of genetic variation, to the discovery
of new classes of regulatory RNAs, the human genome is
even more complex than we understood when its
sequence was declared complete more than 10 years
ago. The more genomes we sequence, the more problems
we will be challenged to solve. However, as we seek to
interpret sequences, the sum total of the knowledge we
have gained thus far propels us forward ever rapidly.
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