By Dr. Joshua Sturgeon and Dr. Ben Appleby
Next Lesson - Genotype, Phenotype, and Inheritance
Core
Chromosome Structure 
The term chromosome refers to a structure that can exist in both replicated and unreplicated forms, with the replicated form consisting of two identical sister chromatids. Note that the familiar X-shaped chromosome in diagrams has already replicated. It is still often just called a chromosome, which can confuse because the same word also covers the unreplicated form. The replicated chromosome contains two identical DNA polymers (long molecules built from repeating units), with each polymer (arm of the ‘X’) referred to as a sister chromatid. A homologous pair is one maternal and one paternal chromosome that carry the same genes. A pair is homologous whether or not the DNA has been replicated.
Image: The structure of a chromosome before (left) and after (right) replication of DNA has occurred. Note that the replicated chromosome contains two sister chromatids.
SimpleMed original by Dr. Joshua Sturgeon
Each chromatid consists of one DNA polymer, with a short (p) arm, and a long (q) arm. Telomeres are located at each end of a chromosome. Telomeres are repeated sequences of DNA (TTAGGG) which protect the chromosome from degradation. They shorten each time a cell divides, and this is thought to limit the number of times most body cells can divide by mitosis (some cells, such as stem cells, can divide far more often).
A centromere is a specialised DNA sequence which links the sister chromatids - centromeres can be found in different places along the length of the chromosome.
Each chromosome is paired in a homologous pair. These pairings are derived from the inherited maternal and paternal genetic material e.g. the maternal chromosome 11 will be in a homologous pair with the paternal chromosome 11. Homologous chromosomes will contain the same genes. Around 99.9% of the DNA sequence is shared between any two humans, but small differences in sequence can result in different alleles. The two chromosomes of a homologous pair may therefore carry different alleles. Inheritance of these alleles leads to varying phenotypes (physical characteristics).
Image: Different centromere locations.
SimpleMed original by Dr. Joshua Sturgeon
Chromosomes are grouped according to size and shape, as shown in the figure below.
Image: (Extension material) Chromosome group classifications.
SimpleMed original by Dr. Joshua Sturgeon
During interphase (the period between cell divisions, when the cell grows and copies its DNA), chromosomes do not exist as shown in the previous two figures (i.e. as rods) but instead as loose filaments of uncondensed chromatin. The chromosomes only take on the appearance of rods (condensed chromosomes) during division once the chromatin condenses together in prophase (the first stage of cell division).
Although the chromatin is uncondensed and free the chromosomes still occupy specific spaces known as chromosome territories. (This is extension material.)
Image: Chromosome territory map.
Creative commons source by Andreas Bolzer, Gregor Kreth, Irina Solovei, Daniela Koehler, Kaan Saracoglu, Christine Fauth, Stefan Müller, Roland Eils, Christoph Cremer, Michael R. Speicher, Thomas Cremer [CC BY 2.5 (https://creativecommons.org/licenses/by/2.5)]
Each chromosome is paired. These pairs are known as homologous chromosomes. Homologous chromosomes contain the same genes, but they may have different variants of the genes (alleles).
Karyotyping is a method of describing the chromosome composition of a patient. The karyotype is recorded in a standard form including chromosome number, sex complement (XX or XY), and any structural changes. Information in a karyotype is separated by a comma without spaces. A karyotype is derived from a metaphase spread, which is a visualisation of all the chromosomes from a cell taken at metaphase (the stage of cell division when the chromosomes are condensed and lined up, so they are easiest to see).
46,XX = Normal Female
46,XY = Normal Male
47,XY,+21 = Male with trisomy 21, also known as Down’s syndrome.
Mitosis is the method of cell division for somatic cells. The process results in two identical daughter cells with the same chromosome content as the parent cell. Mitosis is crucial for growth, regeneration and repair in the human body by allowing for new tissue to be produced.
There are 5 phases of mitosis:
Prophase - centrioles and spindle fibres (protein threads that pull the chromosomes apart) develop; chromatin condenses (coils up tightly) into visible chromosomes. (Genetic replication has already occurred during interphase which precedes cell division.)
Prometaphase - the nuclear envelope (the membrane around the nucleus) dissolves and spindle fibres attach to the kinetochore (the area of the centromere that the spindle fibres grip).
Metaphase - replicated chromosomes line up along the equator of the cell.
Anaphase - sister chromatids are split and are pulled to opposite poles of the cell.
Telophase - nuclear envelope reforms, the cytoplasm begins to cleave. Each sister chromatid is now a separate chromosome.
These phases are followed by cytokinesis, which is the splitting of the cytoplasm which results in the formation of 2 daughter cells.
Mitosis starts with a somatic body cell with 46 chromosomes, organised into 23 pairs. When replication of this DNA occurs, there are still 46 chromosomes, but each one is made up of two chromatids joined by the centromere, making 92 chromatids in this cell. When anaphase occurs, it is the centromere that splits, dividing the two chromatids. This leaves two daughter cells with 46 chromosomes each. Each separated chromatid becomes a chromosome in its own right, so each daughter cell receives one chromatid from each of the 46 replicated chromosomes.
Non-disjunction is the failure of one or more pairs of sister chromatids to separate normally during nuclear division, which results in an abnormal distribution of chromosomes in the daughter cells. In mitosis, this means one of the daughter cells will have 3 copies of one chromosome (trisomy) and one will have only 1 copy (monosomy).
The consequences of mitotic non-disjunction depend on when in early embryonic development the non-disjunction occurs.
The first post-zygotic division is the first cell division in a developing embryo, making two cells from one. If nondisjunction occurs in this division, a trisomy cell (with 47 chromosomes) and a monosomy cell (with 45 chromosomes) will be produced. The monosomy cell will be destroyed leaving only the trisomy cell to divide. From this point onward all cells in the body will now be trisomic. This is a non-mosaic karyotype (every cell has the same chromosomes). If the extra chromosome is chromosome 21, this causes Down’s syndrome. However, most Down’s syndrome is caused by a change in the sperm or egg before fertilisation (see Meiotic Non-disjunction below).
If the non-disjunction event happens during a later cell division a slightly different outcome is produced. As before the monosomy cell is destroyed and a trisomy cell is produced. However, by this point multiple successful divisions have occurred meaning there are also surviving diploid cells. In the long term, some cells in the body will be derived from the trisomy cell line, and the rest will be derived from the healthy, normal diploid cell line. This presence of more than one cell line in the body is called mosaicism. This mosaicism can be spread throughout the tissues of the body if division happened earlier, or may be limited to a specific tissue.
Meiosis is a special form of cell division used for the production of germ cells. The precursor germ cell begins diploid with 46 chromosomes arranged in 23 pairs. Meiosis results in the production of four non-identical cells, each with half the chromosome content of the parent cell, meaning 23 chromosomes (haploid). In meiosis, one round of replication is followed by two rounds of division, which can be split into meiosis I and II.
Meiosis I shares some superficial similarities with mitosis in that the cell progresses through comparable phases, but it is fundamentally different in several key ways:
In mitosis the sister chromatids of a replicated chromosome are pulled apart in anaphase through the splitting of the centromere. For example, the maternal chromosome 11 pair of sister chromatids has its two replicated arms pulled apart, leaving each cell with a single copy of the maternal chromosome. This means that at the end of mitosis, there are two daughter cells with exactly the same DNA.
In meiosis however, during anaphase I (in meiosis I) the homologous pairs (ie the 23 pairs) are pulled apart. Each cell is left with 23 chromosomes, each still made of two sister chromatids, so each cell has 46 chromatids. It also means that genetic information is randomly distributed between the cells: each cell after meiosis I gets a random mix of maternal and paternal chromosomes (independent assortment, see below). For example, the maternal chromosome 11 during anaphase I is pulled away from the paternal chromosome 11 (the other half of its homologous pair).
In meiosis II, the sister chromatids are split through division of the centromere, becoming chromosomes in their own right, leaving each daughter cell with 23 chromosomes (which were chromatids a moment ago).
In summary:
- Stem cell begins with 46 chromosomes arranged in 23 pairs.
- The cell undergoes DNA replication to form 46 chromosomes, each with 2 chromatids, meaning 92 chromatids.
- The cell undergoes first division, dividing the 23 pairs, forming two cells each with 23 chromosomes, formed from 46 chromatids.
- The cell undergoes second division, splitting the centromeres, leaving four daughter cells in total, each with 23 chromosomes (made up of 23 chromatids).
Non-disjunction in meiosis is also a failure of chromosomes to separate, but it can happen at either division: homologous chromosomes may fail to separate in meiosis I, or sister chromatids may fail to separate in meiosis II. The severity of the consequences of meiotic non-disjunction depends on whether the non-disjunction event happens in meiosis I or II. If it occurs in meiosis I, after fertilisation, none of the zygotes will be normal, they will either be trisomic or monosomic.
Image: Non-disjunction in Meiosis 1.
SimpleMed original by Dr. Joshua Sturgeon
If non-disjunction happens in meiosis II, two of the four gametes are normal, one is missing a chromosome and one has an extra chromosome. After fertilisation by a normal gamete, 2 zygotes will be normal, one will be monosomic, and one will be trisomic.
96% of Down’s Syndrome cases are caused by non-disjunction in meiosis.
Image: Non-disjunction in Meiosis 2.
SimpleMed original by Dr. Joshua Sturgeon
The umbrella term for an incorrect number of chromosomes in a body cell (i.e. not 46) is aneuploidy. Aneuploidy can cause a number of genetic conditions, depending on whether chromosomes are missing or in excess, and which specific chromosomes are affected.
Conditions caused by an addition of a single chromosome leading to a total of 47.
- Down’s syndrome: 47,XX,+21 - addition of a chromosome 21 - a total of 3 chromosome 21’s. This karyotype would be for a female patient
- Edwards’ syndrome: 47,XX,+18 - addition of a chromosome 18. This karyotype would be for a female patient. Most babies with full Edwards’ syndrome (an extra chromosome 18 in every cell) unfortunately die before or shortly after birth. Babies with mosaic (only some cells affected) or partial trisomy 18 may have fewer health problems, and some grow up to be adults.
- Patau’s syndrome: 47,XX,+13 - addition of a chromosome 13. This karyotype would be for a female patient. This condition commonly leads to miscarriage, stillbirth or death shortly after birth. More than 9 out of 10 children born with Patau’s syndrome unfortunately die during the first year.
Polyploidy is when an entire extra set of chromosomes is added. Triploidy (three sets) results in a total of 69 chromosomes, for example 69,XXX, 69,XXY or 69,XYY. Most fetuses with triploidy will not survive to term. Triploidy can be caused by two sperm fertilising one egg (dispermy, a type of polyspermy). It can also happen when an egg keeps a whole extra set of chromosomes because a meiotic division fails.
The only monosomy which is compatible with survival to birth is Turner syndrome (monosomy X). Even so, about 99% of pregnancies that start with a 45,X embryo are lost spontaneously, mainly in the first trimester. Turner syndrome results in a karyotype of 45,X or 45,X0 (where 0 denotes lack of a chromosome). All other monosomies are immediately lethal because, apart from the sex chromosomes, two copies of every chromosome are required at all times. Survival with a single X is possible because in females most genes on the second X are switched off (X-inactivation), and males (XY) can survive with one X. However, some genes on the X chromosome escape this switching off, so having only one X still brings abnormalities and symptoms. Almost all patients with Turner syndrome are shorter than average and have underdeveloped ovaries (called streak ovaries), which can affect puberty and cause infertility. All patients with Turner syndrome are female.
Generation of genetic diversity:
Meiosis creates genetic diversity in two ways:
- Crossing-over: The exchange of regions of DNA between 2 homologous chromosomes. It happens in prophase I, at points called chiasmata (where the chromosomes are joined and exchange DNA).
- Independent assortment: the random orientation of each pair of chromosomes along the midline of the cell (ie sometimes the maternal one is on the left, sometimes on the right). This gives each gamete a random mix of maternal and paternal chromosomes.
Spermatogonia (the stem cells that start sperm production) divide by mitosis. Some of the cells they make become primary spermatocytes. Each primary spermatocyte divides by meiosis into 4 spermatids (immature sperm), which then mature into sperm. The whole process takes about 70 days.
Overall, one oogonium divides into 1 mature ovum and 3 polar bodies.
Oogenesis takes many years. Meiosis I starts before birth, then the cells are arrested (paused) in prophase I until after puberty. After puberty, one cell per month completes meiosis I and is released at ovulation as a secondary oocyte, for the rest of a female’s reproductive life. The secondary oocyte pauses again in metaphase of meiosis II and only completes meiosis II if it is fertilised.
Impact of Missegregation in Meiosis:
Missegregation means chromosomes failing to separate correctly. When these errors happen in meiosis, they are major contributors to:
- Miscarriage: aneuploidy (an abnormal number of chromosomes) is the leading genetic cause of pregnancy loss.
- Age-related infertility.
- A leading cause of intellectual disability.
Nondisjunction can occur at two different separation steps. In meiosis I, a homologous chromosome pair travels to the same daughter cell instead of separating. In meiosis II, sister chromatids fail to separate. Either error can produce gametes with one extra chromosome or one missing chromosome. After fertilisation, those gametes can produce a trisomy or monosomy respectively.
The chromosome involved determines whether development can continue. Trisomy 21 causes Down’s syndrome, while trisomies 18 and 13 cause Edwards’ and Patau’s syndromes. These are the principal full autosomal trisomies (extra copies of a numbered chromosome, not X or Y) seen in liveborn children; most other full autosomal aneuploidies result in early pregnancy loss. Sex-chromosome aneuploidies include 45,X, 47,XXY, 47,XXX and 47,XYY. They are often more compatible with survival because only one X chromosome is normally fully active in each somatic cell and the Y chromosome contains relatively few genes. Dosage still matters because some X-linked genes (genes on the X chromosome) escape silencing (being switched off). See Epigenetics, Genomic Imprinting and Mitochondrial Inheritance for X-inactivation and escape from it.
Timing also changes the pattern. Meiotic nondisjunction is present from fertilisation and therefore affects the resulting conceptus (the embryo and the tissues that support it, such as the placenta) throughout. Mitotic nondisjunction after fertilisation can produce two or more cell lines, called mosaicism, when a normal cell line survives alongside the abnormal one. An earlier mitotic error usually distributes the abnormal cell line more widely. Increasing maternal age is associated with meiotic aneuploidy, partly because oocytes remain arrested for years and the cohesion and spindle systems that separate chromosomes become less reliable.
Edited by: Dr. Marcus Judge andDr. Maddie Swannack
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