as copy number variation (CNV).
Copy number variation results from insertions, deletions, and duplications of large
segments of DNA. These segments are big enough to include whole genes. Variation
in gene copy number can influence the activity of genes and ultimately affect many
body functions.
Researchers were surprised to learn that copy number variation accounts for a
significant amount of genetic difference between people. More than 10 percent of
human DNA appears to contain these differences in gene copy number. While
much of this variation does not affect health or development, some differences
likely influence a person’s risk of disease and response to certain drugs. Future
research will focus on the consequences of copy number variation in different parts
of the genome and study the contribution of these variations to many types of
disease.
For more information about copy number variation:
The Howard Hughes Medical Institute discusses the results of recent research on
copy number variation in the news release, Genetic Variation: We’re More Different
Than We Thought (http://www.hhmi.org/news/scherer20061123.html).
For people interested in more technical data, several institutions provide databases
of structural differences in human DNA, including copy number variation:
•
Database of Genomic Variants (http://dgv.tcag.ca/dgv/app/home)
•
The Sanger Institute: Database of Chromosomal Imbalance and
Phenotype in Humans using Ensembl Resources (DECIPHER
(http://decipher.sanger.ac.uk/))
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Can changes in the number of chromosomes affect health
and development?
Human cells normally contain 23 pairs of chromosomes, for a total of 46
chromosomes in each cell (illustration on page 50). A change in the number of chromosomes can cause problems with growth, development, and function of the
body’s systems. These changes can occur during the formation of reproductive
cells (eggs and sperm), in early fetal development, or in any cell after birth. A gain
or loss of chromosomes from the normal 46 is called aneuploidy.
A common form of aneuploidy is trisomy, or the presence of an extra chromosome
in cells. “Tri-” is Greek for “three”; people with trisomy have three copies of a
particular chromosome in cells instead of the normal two copies. Down syndrome
is an example of a condition caused by trisomy (illustration on page 51). People with Down syndrome typically have three copies of chromosome 21 in each cell,
for a total of 47 chromosomes per cell.
Monosomy, or the loss of one chromosome in cells, is another kind of aneuploidy.
“Mono-” is Greek for “one”; people with monosomy have one copy of a particular
chromosome in cells instead of the normal two copies. Turner syndrome is a
condition caused by monosomy (illustration on page 52). Women with Turner syndrome usually have only one copy of the X chromosome in every cell, for a total
of 45 chromosomes per cell.
Rarely, some cells end up with complete extra sets of chromosomes. Cells with
one additional set of chromosomes, for a total of 69 chromosomes, are called triploid
(illustration on page 53). Cells with two additional sets of chromosomes, for a total of 92 chromosomes, are called tetraploid. A condition in which every cell in the
body has an extra set of chromosomes is not compatible with life.
In some cases, a change in the number of chromosomes occurs only in certain
cells. When an individual has two or more cell populations with a different
chromosomal makeup, this situation is called chromosomal mosaicism (illustration
on page 54). Chromosomal mosaicism occurs from an error in cell division in cells other than eggs and sperm. Most commonly, some cells end up with one extra or
missing chromosome (for a total of 45 or 47 chromosomes per cell), while other
cells have the usual 46 chromosomes. Mosaic Turner syndrome is one example
of chromosomal mosaicism. In females with this condition, some cells have 45
chromosomes because they are missing one copy of the X chromosome, while
other cells have the usual number of chromosomes.
Many cancer cells also have changes in their number of chromosomes. These
changes are not inherited; they occur in somatic cells (cells other than eggs or
sperm) during the formation or progression of a cancerous tumor.
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For more information about chromosomal disorders:
A discussion of how chromosomal abnormalities happen (http://www.genome.gov/
11508982#6) is provided by the National Human Genome Research Institute.
The Centre for Genetics Education offers a fact sheet about changes in chromosome
number or size (http://www.genetics.edu.au/Information/Genetics-Fact-Sheets/
Changes-to-Chromosomes-Number-Size-and-Structure-FS6).
Information about chromosomal changes (http://www.eurogentest.org/index.php?
id=611), including changes in the number of chromosomes, is available from
EuroGentest.
The National Organization for Rare Disorders offers an overview of triploid syndrome
(http://www.rarediseases.org/rare-disease-information/rare-diseases/byID/710/
viewAbstract).
Chromosomal Mosaicism (http://mosaicism.cfri.ca/index.htm), a web site provided
by the University of British Columbia, offers detailed information about mosaic
chromosomal abnormalities.
MedlinePlus offers an encyclopedia article about chromosomal mosaicism
(http://www.nlm.nih.gov/medlineplus/ency/article/001317.htm).
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Illustrations
Human cells normally contain 23 pairs of chromosomes, for a total of 46
chromosomes in each cell.
page 50
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Mutations and Health
Trisomy is the presence of an extra chromosome in cells. Down syndrome is
an example of a condition caused by trisomy.
page 51
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Monosomy is the loss of one chromosome in cells. Turner syndrome is an
example of a condition caused by monosomy.
page 52
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Cells with one additional set of chromosomes, for a total of 69 chromosomes,
are called triploid.
page 53
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When an individual has two or more cell populations with a different
chromosomal makeup, this situation is called chromosomal mosaicism.
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Can changes in the structure of chromosomes affect
health and development?
Changes that affect the structure of chromosomes can cause problems with growth,
development, and function of the body’s systems. These changes can affect many
genes along the chromosome and disrupt the proteins made from those genes.
Structural changes can occur during the formation of egg or sperm cells, in early
fetal development, or in any cell after birth. Pieces of DNA can be rearranged within
one chromosome or transferred between two or more chromosomes. The effects
of structural changes depend on their size and location, and whether any genetic
material is gained or lost. Some changes cause medical problems, while others
may have no effect on a person’s health.
Changes in chromosome structure include:
Translocations (illustration: balanced on page 57),
(illustration: unbalanced on page 58)
A translocation occurs when a piece of one chromosome breaks off and
attaches to another chromosome. This type of rearrangement is described
as balanced if no genetic material is gained or lost in the cell. If there is a
gain or loss of genetic material, the translocation is described as unbalanced.
Deletions (illustration on page 59)
Deletions occur when a chromosome breaks and some genetic material is
lost. Deletions can be large or small, and can occur anywhere along a
chromosome.
Duplications (illustration on page 60)
Duplications occur when part of a chromosome is copied (duplicated) too
many times. This type of chromosomal change results in extra copies of
genetic material from the duplicated segment.
Inversions (illustration on page 61)
An inversion involves the breakage of a chromosome in two places; the
resulting piece of DNA is reversed and re-inserted into the chromosome.
Genetic material may or may not be lost as a result of the chromosome breaks.
An inversion that involves the chromosome’s constriction point (centromere)
is called a pericentric inversion. An inversion that occurs in the long (q) arm
or short (p) arm and does not involve the centromere is called a paracentric
inversion.
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Isochromosomes (illustration on page 62)
An isochromosome is a chromosome with two identical arms. Instead of one
long (q) arm and one short (p) arm, an isochromosome has two long arms or
two short arms. As a result, these abnormal chromosomes have an extra
copy of some genes and are missing copies of other genes.
Dicentric chromosomes (illustration on page 63)
Unlike normal chromosomes, which have a single constriction point
(centromere), a dicentric chromosome contains two centromeres. Dicentric
chromosomes result from the abnormal fusion of two chromosome pieces,
each of which includes a centromere. These structures are unstable and often
involve a loss of some genetic material.
Ring chromosomes (illustration on page 64)
Ring chromosomes usually occur when a chromosome breaks in two places
and the ends of the chromosome arms fuse together to form a circular
structure. The ring may or may not include the chromosome’s constriction
point (centromere). In many cases, genetic material near the ends of the
chromosome is lost.
Many cancer cells also have changes in their chromosome structure. These changes
are not inherited; they occur in somatic cells (cells other than eggs or sperm) during
the formation or progression of a cancerous tumor.
For more information about structural changes to chromosomes:
The National Human Genome Research Institute provides a list of questions and
answers about chromosome abnormalities (http://www.genome.gov/11508982), including a glossary of related terms.
Chromosome Deletion Outreach offers a fact sheet on this topic titled Introduction
to Chromosomes (http://www.chromodisorder.org/CDO/General/
IntroToChromosomes.aspx). This resource includes illustrated explanations of
several chromosome abnormalities.
The Centre for Genetics Education provides fact sheets about changes in
chromosome number or size (http://www.genetics.edu.au/Information/Genetics-Fact-Sheets/Changes-to-Chromosomes-Number-Size-and-Structure-FS6) and
chromosomal rearrangements (translocations) (http://www.genetics.edu.au/
Information/Genetics-Fact-Sheets/Changes-to-Chromosome-Structure-
Translocations-FS7).
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EuroGentest offers fact sheets about chromosome changes
(http://www.eurogentest.org/index.php?id=611) and chromosome translocations
(http://www.eurogentest.org/index.php?id=612).
More technical information is available from the textbook Human Molecular Genetics
(second edition, 1999) in the section about structural chromosome abnormalities
(http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hmg.section.196#209).
The Atlas of Genetics and Cytogenetics in Oncology and Haematology provides a
technical introduction to chromosomal aberrations (http://atlasgeneticsoncology.org/
Deep/Chromaber.html) and a detailed discussion of ring chromosomes
(http://atlasgeneticsoncology.org/Deep/RingChromosID20030.html), particularly
their role in cancer.
Illustrations
In a balanced translocation, pieces of chromosomes are rearranged but no
genetic material is gained or lost in the cell.
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An unbalanced translocation occurs when a child inherits a chromosome with
extra or missing genetic material from a parent with a balanced translocation.
page 58
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A deletion occurs when a chromosome breaks and some genetic material is
lost.
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A duplication occurs when part of a chromosome is copied (duplicated)
abnormally, resulting in extra genetic material from the duplicated segment.
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Inversions occur when a chromosome breaks in two places and the resulting
piece of DNA is reversed and re-inserted into the chromosome. Inversions that
involve the centromere are called pericentric inversions; those that do not
involve the centromere are called paracentric inversions.
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An isochromosome is an abnormal chromosome with two identical arms, either
two short (p) arms or two long (q) arms.
page 62
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Dicentric chromosomes result from the abnormal fusion of two chromosome
pieces, each of which includes a centromere.
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Ring chromosomes usually occur when a chromosome breaks in two places
and the ends of the chromosome arms fuse together to form a circular structure.
page 64
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Can changes in mitochondrial DNA affect health and
development?
Mitochondria (illustration on page 7) are structures within cells that convert the energy from food into a form that cells can use. Although most DNA is packaged
in chromosomes within the nucleus, mitochondria also have a small amount of their
own DNA (known as mitochondrial DNA or mtDNA). In some cases, inherited
changes in mitochondrial DNA can cause problems with growth, development, and
function of the body’s systems. These mutations disrupt the mitochondria’s ability
to generate energy efficiently for the cell.
Conditions caused by mutations in mitochondrial DNA often involve multiple organ
systems. The effects of these conditions are most pronounced in organs and tissues
that require a lot of energy (such as the heart, brain, and muscles). Although the
health consequences of inherited mitochondrial DNA mutations vary widely,
frequently observed features include muscle weakness and wasting, problems with
movement, diabetes, kidney failure, heart disease, loss of intellectual functions
(dementia), hearing loss, and abnormalities involving the eyes and vision.
Mitochondrial DNA is also prone to somatic mutations, which are not inherited.
Somatic mutations occur in the DNA of certain cells during a person’s lifetime and
typically are not passed to future generations. Because mitochondrial DNA has a
limited ability to repair itself when it is damaged, these mutations tend to build up
over time. A buildup of somatic mutations in mitochondrial DNA has been associated
with some forms of cancer and an increased risk of certain age-related disorders
such as heart disease, Alzheimer disease, and Parkinson disease. Additionally,
research suggests that the progressive accumulation of these mutations over a
person’s lifetime may play a role in the normal process of aging.
For more information about conditions caused by mitochondrial DNA mutations:
Genetics Home Reference provides background information about mitochondria
and mitochondrial DNA (http://ghr.nlm.nih.gov/handbook/basics/mtdna) written in consumer-friendly language.
The Cleveland Clinic offers a basic introduction to mitochondrial disease
(http://my.clevelandclinic.org/disorders/Mitochondrial_Disease/hic_Myths_and_
Facts_About_Mitochondrial_Diseases.aspx).
An overview of mitochondrial disorders (http://www.ncbi.nlm.nih.gov/books/
NBK1224/) is available from GeneReviews.
The Muscular Dystrophy Association offers an introduction to mitochondrial disorders
as part of their fact sheet called Mitochondrial Myopathies (http://mda.org/disease/
mitochondrial-myopathies).
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The Neuromuscular Disease Center at Washington University provides an in-depth
description of many mitochondrial conditions (http://neuromuscular.wustl.edu/
mitosyn.html).
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What are complex or multifactorial disorders?
Researchers are learning that nearly all conditions and diseases have a genetic
component. Some disorders, such as sickle cell anemia and cystic fibrosis, are
caused by mutations in a single gene. The causes of many other disorders, however,
are much more complex. Common medical problems such as heart disease,
diabetes, and obesity do not have a single genetic cause—they are likely associated
with the effects of multiple genes in combination with lifestyle and environmental
factors. Conditions caused by many contributing factors are called complex or
multifactorial disorders.
Although complex disorders often cluster in families, they do not have a clear-cut
pattern of inheritance. This makes it difficult to determine a person’s risk of inheriting
or passing on these disorders. Complex disorders are also difficult to study and
treat because the specific factors that cause most of these disorders have not yet
been identified. Researchers continue to look for major contributing genes for many
common complex disorders.
For more information about complex disorders:
A fact sheet about the inheritance of multifactorial disorders
(http://www.genetics.edu.au/Information/Genetics-Fact-Sheets/Environmetal-and-
Genetic-Interactions-Complex-Patterns-of-Inheritance1-FS11) is available from the
Centre for Genetics Education.
If you would like information about a specific complex disorder such as diabetes or
obesity, MedlinePlus (http://www.nlm.nih.gov/medlineplus/) will lead you to fact sheets and other reliable medical information. In addition, the Centers for Disease
Control and Prevention provides a detailed list of diseases and conditions
(http://www.cdc.gov/DiseasesConditions/) that links to additional information.
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What does it mean to have a genetic predisposition to a
disease?
A genetic predisposition (sometimes also called genetic susceptibility) is an
increased likelihood of developing a particular disease based on a person’s genetic
makeup. A genetic predisposition results from specific genetic variations that are
often inherited from a parent. These genetic changes contribute to the development
of a disease but do not directly cause it. Some people with a predisposing genetic
variation will never get the disease while others will, even within the same family.
Genetic variations can have large or small effects on the likelihood of developing
a particular disease. For example, certain mutations in the BRCA1 or BRCA2 genes
greatly increase a person’s risk of developing breast cancer and ovarian cancer.
Variations in other genes, such as BARD1 and BRIP1, also increase breast cancer
risk, but the contribution of these genetic changes to a person’s overall risk appears