A genetically normal human has a maternal copy and a paternal copy of 23 different chromosomes. With 23 pairs of each chromosome, a genetically normal human has 46 chromosomes total. There are exceptions — for example, sperm cells are haploid and contain only one copy of each chromosome (23 chromosomes total). The number of chromosomes within a haploid cell is referred to as n. Thus, a cell with 2 copies of each chromosome (a diploid cell) has 2n chromosomes; a cell with 3 copies of each chromosome (a triploid cell) has 3n chromosomes; and a cell with 4 copies of each chromosome (a tetraploid cell) has 4n chromosomes.
Not including reproductive cells, if an individual has any other than 2n chromosomes then they are heteroploid. If a heteroploid has an exact multiple of n chromosomes (such as 69 or 92, in humans) then that individual is euploid. If a heteroploid does not have an exact multiple of n chromosomes (such as 45, 47 or any value ≠ 46) then that individual is aneuploid. Although rare, triploidy and tetraploidy are forms of euploidy. Paternal chromosome triploids (individuals with an extra copy of every paternal chromosome) have abnormal placentas and are known as partial hydatiform moles; however, maternal chromosome triploids are spontaneously aborted early during gestation.
Aneuploidy is more common than euploidy. Most aneuploidy is trisomy (three copies of an individual chromosome, instead of a pair) or monosomy (one copy of an individual chromosome). The most common trisomy is trisomy 21, which occurs in 95% of Down Syndrome patients. Chromosomes 21, 13 and 18 contain the fewest genes of any other chromosome — trisomy of any chromosome other than these three deadly. Monosomy of any chromosome except Chromosome X (a condition called Turner Syndrome) is lethal. Aneuploidy is usually caused by meiotic nondisjunction, meaning that (usually during meiosis I) chromosomes fail to disjoin properly and daughter cells either have too many or too few chromosomes.
Chromosome structure abnormalities can be either unbalanced rearrangements or balanced rearrangements. The various kinds of unbalanced rearrangements are detailed below. Unbalanced rearrangements involve deletion, duplication or both. Deletion of a chromosome segment leads to partial monosomy of that segment. Duplication of a chromosome segments leads to partial trisomy of that segment. Any mutation leading to an imbalance like monosomy, trisomy or other can result in an abnormal phenotype.
| Kind | Overview |
|---|---|
| Deletions |
A deletion is loss of a chromosome segment. There are two kinds of deletions: terminal, at the end of a chromosome; and interstitial, along a chromosome arm. Deletions can occur if a chromosome simply breaks and part of it floats away. Also, deletions can occur of misaligned chromatids cross over unequally. In addition, deletions can occur if balanced translocations or inversions segregate abnormally. A carrier individual — with one chromosome carrying the deletion, and another chromosome lacking the deletion — is monosomic for the affected genes. Monosomy usually leads to haploinsufficiency, which arises when two copies of a gene are necessary and only one copy is insufficient. Monosomy of a hormone-encoding gene is usually haploinsufficient, since one gene copy cannot encode for enough production of that hormone. |
| Duplications | Duplications, like deletions, can arise by unequal crossing over or abnormal segregation. Phenotypic abnormalities can arise if the duplication results in an extra gene copy (partial trisomy), leading to over-expression. Also, duplications within a gene can destroy its function, thus leading to haploinsufficiency. |
| Markers & Rings |
Marker chromosomes (aka supernumary chromosomes or extra structurally abnormal chromosomes) are very small and unnamed chromosomes which usually exist in addition to a normal diploid. Marker chromosomes usually consist of just centromeric heterochromatin. Larger marker chromosomes, though, contain some material from one or both chromosome arms; this disruption can lead to phenotypic abnormalities. Neocentromeres are marker chromosomes stable during mitosis which lack centromeric DNA, but which somehow have centromere activity. When a chromosome undergoes two breaks, chromosomal DNA can separate and form a ring structure. This form of marker is known as a ring chromosome. Although quite rare, ring chromosomes containing centromeric DNA are mitotically stable. However, sometime sister ring chromatids can tangle while trying to separate during anaphase. This tangling can lead to breakage, resulting in demise of the ring chromosome or even causing new ring chromosomes to form of unequal size. Thus, ring chromosomes are rarely found in all of an organism’s cells. High-resolution banding is ineffective at detecting marker chromosomes because most makers are too small to even discern the bands. However, FISH using probes for centromeric heterochromatin can usually visualize marker chromosomes. |
| Isochromosomes | Isochromosomes arise when one arm of a chromosome goes missing, and the remaining arm is duplicated to form a mirror image. In a diploid cell, this leads to partial trisomy of the genetic material from one arm (the duplicate arms, and arm on the homologous chromosome) and partial monosomy of the genetic material from the other arm. |
| Dicentrics | Although very rare, a dicentric occurs when centromere-containing fragments fuse together to form a new chromosome with two centromeres. Dicentrics can be mitotically stable if one centromere is inactivated, or if the chromosome is pseudodicentric. A pseuodicentric chromosome has centromeres which move to only one pole or the other during anaphase. |
High-resolution banding can detect deletions and duplications on the magnitude of several thousand base-pairs, and FISH can detect very small or uncertain deletions.
Chromosome structure abnormalities can be either unbalanced rearrangements or balanced rearrangements. Balanced rearrangements usually do not lead to phenotypic abnormalities; all genetic information is present in the right amount, just in a different order or in the wrong location.
| Kind | Overview |
|---|---|
| Inversions |
An inversion occurs in two steps: a chromosome breaks in two locations; the chromosome refuses with the segment between the breaks inverted. When both breaks are in the same arm, the inversion is paracentric; when there is one break in each arm, the inversion is pericentric. Paracentric inversions do not usually affect phenotype, and are hard to detect using banding or FISH. However, offspring of an inversion carrier are at risk because a loop forms when paternal and maternal chromosomes cross over; aberrant recombinations can occur within this inversion loop. Pericentric inversions, though, can lead to unbalanced gametes with duplication and deficiency of chromosome segments. |
| Translocations |
Translocation is the exchange of chromosome segments, usually between nonhomologous chromosomes. There are two primary types of translocations: reciprocal translocations and Robertsonian translocations. A reciprocal translocation occurs when segments from nonhomologous chromosomes break off, with segment attaching to the other chromosome and vice-versa. A Robertsonian translocation occurs when two acrocentric chromosomes (chromosomes with tiny short arms, meaning the centromere is near one end) fuse at the centromere and lose their short arms. Reciprocal translocations usually involve only two chromosomes, meaning the total chromosome number is unchanged. Reciprocal translocation are typically harmless, despite being more common in individuals so retarded that they require institutional care. There are three kinds of reciprocal translocation: alternate; adjacent-1; and adjacent-2. Robertsonian translocations lead to a balanced karyotype with only 45 chromosomes. Because acrocentric short arms contain just multiple copies of ribosomal RNA genes, loss of acrocentric short arms is not phenotypically important. A third type of translocation — an insertion — occurs when a segment from one chromosome inserts into a different chromosome (either in its original orientation, or inverted). Inversion translocations are rare because they require three chromosome breaks. Abnormal segretation in insertion carriers can lead to offspring with deletions or duplications of the inserted segment. Alternatively, offspring can be normal or balanced carriers. |
A mutation is any change in the nucleotide sequence or arrangement of DNA; mutations are one of only four evolutionary agents. There are three categories of mutations: genome mutations, which arise from chromosome missegregation and change how many intact chromosomes are in a cell, leading to aneuploidy; chromosome mutations, which arise from chromosome rearrangement and restructure an individual chromosome; and gene mutations, which are base pair mutations affecting an individual gene. An inherited mutation is a mutation passed on from ancestors; a de novo mutation is a new and non-inherited mutation. Disease mutations interfere with protein synthesis at one of the steps in the list to the bottom right.
Somatic mutations are not passed on to progeny and only affect some cells of the body; a tumor is a common example of a somatic mutation. Germline mutation affect germ cells (cells which differentiate into eggs or sperm) and are passed onto progeny. Many germline mutations occur either in the fertilized egg (the zygote), leading to both germ and somatic cells containing the mutation. Dynamic mutations worsen during gametogenesis, leading to a worsened phenotype in each generation. Examples of dynamic mutations include Huntington Disease and Fragile X Syndrome, which involve repeat sequences extending during gametogenesis.
Some mutations are more likely to be maternal and other mutations are more likely to be paternal. Primary oocytes develop fetally and ovulate years and decades later; the older an oocyte is, the more likely it is to undergo nondisjunction. This nondisjunction leads to trisomy (which can be viable) and monosomy (which is almost never viable). For this reason, aneuploidy is maternal in at least 80% of all cases and occurs more often with maternal age. On the other hand, spermatogenesis occurs throughout a man’s entire life. With mutations accumulating during each round of replication, point mutations are almost always paternal and increase with paternal age.
Point mutations are substitutions of one base pair for another. A transition is when one pyrimidine is swapped for another — such as C for T, or T for C — or one purine is swapped for another — such as A for G, or G for A. A transversion is when a pyrimidine and a purine swap. Transitions are more frequent because when cytosines methylate to form 5-methylcytosine, they can spontaneously deaminate to thymidine.
| Missense Mutation | A missense mutation is the changing of a single base-pair. Within a coding region, this usually leads to a change of a single amino acid in the protein product. However, if this mutation is in the 5′ or 3′ untranslated region then a missense can lead to underexpression of the protein product. |
|---|---|
| Nonsense Mutation | A nonsense mutation (aka chain termination mutation) is the replacement of a codon encoding an amino acid with a stop codon. This stop codon ends transcription of that gene prematurely, with an incomplete and unstable mRNA formed. Most of these mRNAs just fall apart; however, the few that are translated result in truncated proteins that quickly disintegrate. |
| RNA Processing Mutation | An RNA processing mutation interferes with splicing of mRNA. If the point mutation alters a splice donor or splice acceptor site, then RNA splicing is interfered with or abolished at that location. If the point mutation creates a new splice donor or splice acceptor site, then this new site competes with normal splicing and the processed mRNA might still contain introns. |
There are deletions (removal of DNA), insertions (addition of DNA), inversions (reversal of the orientation of a DNA segment), translocations (moving of a DNA segment) and combinations thereof. Some deletions and insertions are small changes which are detectable only via PCR or genome sequencing; these usually shift the reading frame (a frameshift mutation) and lead to truncation of the mRNA by an early stop codon in the new reading frame. Some larger mutations can be detected via Southern blotting. For a mutation to be detectable by chromosome banding, it must involve at least 2 million base pairs.
Deletions, insertions, inversions and translocations often arise via faulty recombination. For example, unequal crossing over is crossing over without proper exchange of genetic information, leading to insertions in one chromosomes and deletions in another. Another form of faulty recombination is when mispaired chromosomes or sister chromatids exchange genetic information.
| Mutation | Example | Overview |
| Missense | Phe15Tyr | A missense mutation is described by the wild-type amino acid, its residue and the resulting mutant amino acid. The example shows a mutation where a phenylalanine is converted to tyrosene at residue 15 of a gene. |
|---|---|---|
| Nonsense | Ser25X | A nonsense mutation is described by the wild-type amino acid, its residue and then an X to represent the mutant stop codon. The example shows a mutation where serine is replaced with a stop codon at residue 25 of a gene. |
| Nucleotide Change | g.3000G>A c.1000g>a |
If the full genomic sequence is known, a nucleotide change is denoted by a prefix (g for genomic and c for cDNA), followed by the number of that nucleotide, the original nucleotide, a ‘>’ symbol, and finally the mutant nucleotide. Mutations identified in genomic DNA are denoted with capitalized nucleotides; mutations identified in non-genomic DNA are denoted with lower-case nucleotides. The first example shows a genomic mutation at position 3,000 where a G transitions to an A; and the second example shows the same mutation at position 1,000 on cDNA. |
| g.IVS25+2G>A g.IVS25-2T>A g.IVS25-2A>T |
If the full genomic sequence is not known, then nucleotides are counted either: up from the 5′ splice donor site, with +1 being the invariant G of the GT at the 5′ splice donor site; or down from the 3′ splice acceptor site, with -1 being the invariant G of the AG at the 3′ splice acceptor site. The first example shows a transversion at the T of the 5′ splice donor site; the second example shows a transversion at the A of the 3′ splice acceptor site. | |
| Deletions | c.1000_10003delGCAT | Small deletions begin with a prefix (g or c for genomic or cDNA), followed by the locations of the deleted nucleotides, then a del for deletion, and finally the nucleotides deleted. The example shows a four-nucleotide deletion of a G,C, A and T at respective locations 1000, 1001, 1002 and 1003. |
| Insertions | c.1000_10001insATGC | Small insertions begin with a prefix (g or c for genomic or cDNA), followed by the nucleotides flanking the insertion, then an ins for insertion, and finally the nucleotides inserted. The example shows an insertion of A,T,G and C between nucleotides 1000 and 1001. |
| Nomenclature table derived from Nussbaum, McInnes & Willard: Genetics in Medicine, 7th ed. Philadelphia, Saunders, 2007. (pg 181) | ||
| Effect | Example | Overview |
| Loss of Function | α-thalassemia β-thalassemia Turner Syndrome Retinoblastoma |
Loss of function mutations leads to a lower gene dosage. Examples of loss of function diseases are the α-thalassemias (where the entire α-globin gene is deleted), β-thalassemias (premature stop codon or coding missense), Turner Syndrome (a monosomy where a chromosome is lost) and retinoblastoma (where a somatic mutation lead to loss of function of tumor-suppressor genes). Many loss-of-functional diseases are less severe in heterozygotes; oftentimes, a single functional allele is enough for a healthy or mild-diseases phenotype. |
|---|---|---|
| Gain of Function | Trisomy 21 Charcot-Marie-Tooth 1A Hemoglobin Kempsey Achondroplasia |
Gain of function mutations lead to increased activity of a certain protein in tissues which normally express it (as opposed to heterocrhonic or ectopic expression). This increased activity can be due to a higher gene dosage, as in Down Syndrome (a third copy of part or all of Chromosome 21) or Charcot-Marie Tooth Type 1A (duplication of a particular gene) or even progression of certain cancers. Alternatively, one function of a protein might be detrimentally hyperactive. Examples include: hemoglobin Kempsey, a mutant hemoglobin with such high oxygen affinity that it does not release oxygen to tissues; and achondroplasia, where an over-strong signal (from exceptional binding of a growth factor receptor) leads to growth retardation. |
| Novel Property | Sickle Cell | Novel property mutations give encoded proteins new properties. For example, the hemoglobin chains of sickle cells aggregate into long fibers which deform the cell and impair its function. Some novel property mutations are also loss of function mutations; mutants with novel glycosylation sites are rendered inactive by glycosylation. |
| Heterochronic & Ectopic Expression |
Some Cancers | Certain mutations are simply due to gene expression at the wrong time (heterochronic) or in the wrong tissue (ectopic). For example, constitutive expression of proliferation genes (known as oncogenes) can lead to tumor formation. |
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