Aneuploidy and nondisjunction. Down syndrome and related disorders. Chromosomal rearrangements.

Introduction

Some things just work well in pairs. Everyday examples include shoes, gloves, and the earbuds on a music player. If you're missing one member of a pair, it's likely to be a nuisance, and might even be a serious problem (for instance, if you're already late for school!).
Pairs are important in genetics, too. Most of your cells contain 46 chromosomes, rod-like structures made of DNA and protein, that come in 23 perfectly matched pairs. These chromosomes carry tens of thousands of genes, which told your body how to develop and keep it functioning from moment to moment during your lifetimestart superscript, 1, end superscript.
False-colored image of the paired chromosomes of the human genome. The image illustrates that human chromosomes come in homologous pairs, and that each pair is made up of two chromosomes that resemble each other (and look different from the other chromosomes in the cell).
Image credit: "Human genome," by Webridge (CC BY 2.0.
If a chromosome pairs loses or gains a member, or even part of a member, the delicate balance of the human body may be disrupted. In this article, we’ll examine how changes in chromosome number and structure come about, and how they can affect human health.

Aneuploidy: Extra or missing chromosomes

Changes in a cell's genetic material are called mutations. In one form of mutation, cells may end up with an extra or missing chromosome.
Each species has a characteristic chromosome number, such as 46 chromosomes for a typical human body cell. In organisms with two full chromosomes sets, such as humans, this number is given the name 2, n. When an organism or cell contains 2, n chromosomes (or some other multiple of n), it is said to be euploid, meaning that it contains chromosomes correctly organized into complete sets (eu- = good).
If a cell is missing one or more chromosomes, it is said to be aneuploid (an- = not, "not good"). For instance, human somatic cells with chromosome numbers of left parenthesis, 2, n, minus, 1, right parenthesis, equals, 45 or left parenthesis, 2, n, plus, 1, right parenthesis, equals, 47 are aneuploid. Similarly, a normal human egg or sperm has just one set of chromosomes (n, equals, 23). An egg or sperm with left parenthesis, n, minus, 1, right parenthesis, equals, 22 or left parenthesis, n, plus, 1, right parenthesis, equals, 24 chromosomes is considered to be aneuploid.
Two common types of aneuploidy have their own special names:
  • Monosomy is when an organism has only one copy of a chromosome that should be present in two copies left parenthesis, 2, n, minus, 1, right parenthesis.
  • Trisomy is when an organism has a third copy of a chromosome that should be present in two copies left parenthesis, 2, n, plus, 1, right parenthesis.
Diagram illustrating euploidy and aneuploidy.
Euploid cell: a human cell with the normal chromsome number, 2n = 46. The chromosomes are arranged in 23 pairs.
Aneuploid cell, example 1: monosomy. A human cell with a missing chromosome, in this case, chromosome 3. All the other chromosomes are still arranged in pairs of two, but there is just one copy of chromosome 3. The chromosome number of this cell is 2n-1 = 45.
Aneuploid cell, example 2: trisomy. A human cell with an extra chromosome, in this case, an extra copy of chromosome 3. All the other chromosomes are still arranged in pairs of two, but there are three copies of chromosome . The chromosome number of this cell is 2n+1 = 47.
Image modified from "NHGRI human male karyotype," by the National Human Genome Research Institute (public domain.
Aneuploidy also includes cases where a cell has larger numbers of extra or missing chromosomes, as in left parenthesis, 2, n, minus, 2, right parenthesis, comma, left parenthesis, 2, n, plus, 3, right parenthesis, etc. However, if there is an entire extra or missing chromosome set (e.g., 3, n), this is not formally considered to be aneuploidy, even though it may still be bad for the cell or organism. Organisms with more than two complete sets of chromosomes are said to be polyploid.

Nondisjunction of chromosomes

Disorders of chromosome number are caused by nondisjunction, which occurs when pairs of homologous chromosomes or sister chromatids fail to separate during meiosis I or II (or during mitosis).
Meiosis I. The diagram below shows how nondisjunction can take place during meiosis I if homologous don't separate, and how this can lead to production of aneuploid gametes (eggs or sperm):
Diagram depicting nondisjunction in meioisis I. One pair of homologous chromosomes fail to separate during meiosis I, leading to two abnormal cells as products of meiosis I: one cell with an extra chromosome and one with a missing chromosome. In meiosis II, the chromatid of the chromosomes are separated normally. This leads to production of two gametes with an extra chromosome (n+1 gametes) and two gametes with a missing chromosome (n-1 gametes).
Meiosis II. Nondisjunction can also happen in meiosis II, with sister chromatids (instead of homologous chromosomes) failing to separate. Again, some gametes contain extra or missing chromosomes:
Diagram depicting nondisjunction in meioisis II. Homologous chromosomes separate normally during meiosis I. However, the sister chromatids of one chromosome fail to separate during meiosis II, and instead move to the same pole of the cell and are segregated into the same gamete. In this case, the products of meiosis are two normal, euploid gametes (n), one gamete with an extra chromosome (n+1), and one gamete with a missing chromosome (n-1).
Mitosis. Nondisjunction can also happen during mitosis. In humans, chromosome changes due to nondisjunction during mitosis in body cells will not be passed on to children (because these cells don't make sperm and eggs). But mitotic non-disjunction can cause other problems: cancer cells often have abnormal chromosome numbersstart superscript, 2, end superscript.
Diagram depicting nondisjunction in mitosis. One pair of sister chromatids fail to separate normally and instead move to the same pole of the dividing cell and are segregated into the same daughter cell. This error results in one daughter cell with an extra chromosome (2n+1) and one daughter cell with a missing chromosome (2n-1).
When an aneuploid sperm or egg combines with a normal sperm or egg in fertilization, it makes a zygote that is also aneuploid. For instance, if a sperm cell with one extra chromosome (n, plus, 1) combines with a normal egg cell (n), the resulting zygote, or one-celled embryo, will have a chromosome number of 2, n, plus, 1.
Diagram of a fertilization event in which a normal egg (n) combines with an aneuploid sperm (n +1). The zygote formed by fertilization is aneuploid (2n +1).

Genetic disorders caused by aneuploidy

Human embryos that are missing a copy of any autosome (non-sex chromosome) fail to develop to birth. In other words, human autosomal monosomies are always lethal. That's because the embryos have too low a "dosage" of the proteins and other gene products that are encoded by genes on the missing chromosomestart superscript, 3, end superscript.
Most autosomal trisomies also prevent an embryo from developing to birth. However, an extra copy of some of the smaller chromosomes (13, 15, 18, 21, or 22) can allow the affected individual to survive for a short period past birth, or, in some cases, for many years. When an extra chromosome is present, it can cause problems in development due to an imbalance between the gene products from the duplicated chromosome and those from other chromosomesstart superscript, 3, end superscript.
The most common trisomy among embryos that survive to birth is Down syndrome, or trisomy 21. People with this inherited disorder have short stature and digits, facial distinctions including a broad skull and large tongue, and developmental delays. Here is a karyotype, or image of the chromosomes, from a person with Down syndrome, showing the characteristic three copies of chromosome 21:
Karyotype of a male human with Down syndrome. Most pairs of autosomes, and the X-Y pair of sex chromosomes, are normal. However, chromosome 21 is present in three copies.
Image credit: "21 trisomy - Down syndrome," by the U.S. Department of Energy Human Genome Program (public domain).
About 1 in every 800 newborns is born with Down syndromestart superscript, 4, end superscript. However, the likelihood that a pregnancy will result in an embryo with Down syndrome goes up with a woman's age, particularly above 40 yearsstart superscript, 5, comma, 6, end superscript. This is probably because of more frequent nondisjunction in the developing eggs of older women.
Graph depicting the increase in frequency of Down syndrome with maternal age. X-axis, mother's age (years, 20-45); Y-axis, risk of Down syndrome in live births (%, 0-3.75).
20 years - 0.1 % 25 years - 0.1 % 30 years - 0.2 % 35 years - 0.5 % 40 years - 0.8 % 45 years - 3.6 %
Image credit: "Chromosomal basis of inherited disorders," by OpenStax College, Biology (CC BY 3.0).
In human women, the precursors of the egg cells (called primary oocytes) form very early in life, when the woman herself is still an embryo. Although primary oocytes start meiosis at this early stage, they don’t complete it. Instead, they pause in prophase I, where they remain for many years.
When a woman's body prepares to ovulate as part of the menstrual cycle, one of these long-paused primary oocytes will complete meiosis to produce an egg cell. Primary oocytes that have been paused in prophase I for a long time (say, in a 40-year-old woman) have a greater risk of abnormal chromosome segregation (nondisjunction) when they re-start meiosis than primary oocytes that have been paused in prophase I for a shorter time (say, in a 20-year-old woman)start superscript, 7, end superscript.
Human genetic disorders can also be caused by aneuploidies involving sex chromosomes. These aneuploidies are better-tolerated than autosomal ones because human cells have the ability to shut down extra X chromosomes in a process called X-inactivation. You can learn more in the article on X chromosome inactivation.

Chromosomal rearrangements

In another class of large-scale mutations, big chunks of chromosomes (but not entire chromosomes) are affected. Such changes are called chromosomal rearrangements. They include:
  • A duplication, where part of a chromosome is copied.
  • A deletion, where part of a chromosome is removed.
  • An inversion, where chromosomal region is flipped around so that it points in the opposite direction.
    Diagram schematically representing a deletion, duplication, and inversion.
    Deletion: a region of the original chromosome is removed, leading to a shorter chromosome missing a section.
    Duplication: a region of the original chromosome is duplicated, leading to a longer chromosome with an extra copy of a particular section.
    Inversion: a region of the original chromosome separates from the rest of the chromosome and is replaced in its original spot, but in the opposite orientation,
    Image modified from "Chromosomenmutation," by Deitzel66, modified from NIH Talking Glossary of Genetics (public domain).
  • A translocation, where a piece of one chromosome gets attached to another chromosome. A reciprocal translocation involves two chromosomes swapping segments; a non-reciprocal translocation means that a chunk of one chromosome moves to another.
    Diagram schematically representing reciprocal and non-reciprocal translocations.
    Reciprocal translocation: two non-homologous chromosomes swap fragments. No genetic material is lost, but the resulting chromosomes are hybrids, each containing segments normally found on a different chromosome.
    Non-reciprocal translocation: a fragment is removed from a donor chromosome and inserted into a recipient chromosome. The donor chromosome loses a region, while the recipient chromosome gains a region not normally found on that chromosome.
    Image modified from "Chromosomenmutation," by Deitzel66, modified from NIH Talking Glossary of Genetics (public domain).
In some cases, a chromosomal rearrangement causes symptoms similar to the loss or gain of an entire chromosome. For instance, Down syndrome is usually caused by a third copy of chromosome 21, but it can also occur when a large piece of chromosome 21 moves to another chromosome (and is passed on to offspring along with a regular chromosome 21)start superscript, 4, end superscript. In other cases, rearrangements cause unique disorders, ones that are not associated with aneuploidy.

Attribution:

This article is a modified derivative of "Chromosomal basis of inherited disorders," by OpenStax College, Biology, CC BY 4.0. Download the original article for free at http://cnx.org/contents/185cbf87-c72e-48f5-b51e-f14f21b5eabd@10.53.
This article is licensed under a CC BY-NC-SA 4.0 license.

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