Glossary

Amniocentesis: A type of prenatal diagnostic test. Performed under ultrasound guidance, typically at around 15–16 weeks, although it can be a little earlier or a lot later in pregnancy. A long needle is passed through the woman’s abdomen, and a sample of amniotic fluid is taken. Amniotic fluid is the liquid in which the baby floats. It contains cells that come from the baby. Nowadays, most testing on amniotic fluid is DNA-based and involves directly extracting DNA from these cells or growing (culturing) them in the lab, then extracting the DNA. They can then be used to test for chromosomal abnormalities or other genetic conditions. Old-school chromosome analysis can also be done on the cells (looking at the chromosomes under the microscope), as can other types of testing. For instance, biochemical testing can be done on the cells, or on the fluid itself. These are becoming much less common, however.

Autosomal dominant: A form of inheritance in which there is a change in a gene on one of the autosomes, i.e. chromosomes 1–22, and this is sufficient to cause a genetic condition. You can think of this as the faulty copy of the gene ‘dominating’ over the other, ‘normal’ copy. A person who has an autosomal dominant condition has a 1 in 2 chance of passing this on to each of his or her children. Dominant conditions generally affect males and females equally, although there are some that mainly affect one or the other sex. For example, familial breast and ovarian cancer due to variants in the genes BRCA1 or BRCA2 is a condition that does increase the risk of some cancers (including breast cancer) in men, but mainly affects women. Dominant conditions tend to vary a great deal between affected people, even people in the same family who share the same variant in the relevant gene.

Autosomal recessive: A form of inheritance in which there is a change in both copies of a gene on one of the autosomes, i.e. chromosomes 1–22. If a person is affected by an autosomal recessive condition, it is nearly certain that both of his or her parents is a carrier for the condition — i.e. they have one faulty and one ‘normal’ copy of the gene. There are some very rare circumstances in which one (or, in theory, even both) parents is not a carrier but a child is still affected. For example, there could be a new change in the copy of the gene passed on by the parent who is not a carrier. This is something that happens very rarely for most genes, but there are exceptions; spinal muscular atrophy is one condition in which — although it’s far from common — we do sometimes see affected children who have only one parent who is identified as a carrier. Virtually everyone is a carrier for one to several autosomal recessive conditions. This is almost never an issue for the carrier’s health, although again there are rare exceptions.

Autosome: Any of the chromosomes other than the X and Y. Chromosomes 1–22 are all autosomes.

Centromere: Part of a chromosome. Visible in pictures of chromosomes as the ‘waist’ of some chromosomes, although the centromere can be at one end of the chromosome as well (this is called an acrocentric chromosome, because the centromere is at the peak (‘acro’) of the chromosome. The centromere has an important role in cell division.

Channel: The cell membrane is carpeted with proteins, or complexes of multiple proteins, which function as channels. These allow specific substances, such as potassium ions, to pass across the cell membrane. Sometimes this is a passive process and sometimes an active pumping. Normal functioning of these channels is important for maintaining the right mixture of salts inside and outside cells and for regulating the electrical activity on the surface of cells.

Chorionic villus sampling (CVS): A type of prenatal diagnostic test in which a sample of the placenta is collected — specifically, the chorionic villi. Typically done at around 11–12 weeks of pregnancy. Under ultrasound guidance, a needle is passed through the woman’s abdomen, or sometimes a flexible tube is passed through the placenta, and suction is used to collect the sample. The idea behind the test is that, early in embryonic development, there is a split between the cells that go on to form the fetus, and ultimately the baby, and those that form the placenta, but they start from the same point and share their initial genetic make-up. Genetic test results from the placenta are usually an accurate representation of the fetus, but sometimes there can be changes (especially chromosomal abnormalities) that occur after the split. This usually shows up as apparent chromosomal mosaicism at CVS. If there is mosaicism that is only in the placenta, it’s called confined placental mosaicism. Usually, this is harmless, although occasionally it can affect the function of the placenta. This means that, if we find a mosaic chromosomal abnormality at CVS, we often have to follow up with an amniocentesis to work out the significance of the result.

Chromosome: Chromosomes are structures found in the nucleus of the cell. They are made of very long strands of DNA, wrapped around proteins called histones. The human genome is arranged into 23 pairs of chromosomes (in most people); you inherit one of each pair from each of your parents. The chromosomes are numbered from 1–22 (the autosomes) plus the X and Y chromosomes (the sex chromosomes). If you have missing or extra chromosome material, that means you have missing or extra copies of genes, which can cause chromosomal disorders.

Coding: DNA that is coding is translated into proteins; non-coding DNA is not. Within a gene, the coding parts are the exons, whereas the non-coding parts are the introns as well as regulatory sequences before and after the exons (the 5’, pronounced ‘five prime’, and 3’ untranslated regions). Non-coding DNA may still be transcribed, i.e. copied to RNA. The resulting RNA molecules may have a variety of functions, including signalling and regulating the action of genes.

de novo: Occurring in a child but not in his or her parents. A new change in the DNA.

DNA: Deoxyribonucleic acid — the stuff of life. DNA consists of a long chain of individual bases — adenine, cytosine, guanine, and thymine. These have a sugar backbone, deoxyribose; DNA forms a chain by linking deoxyribose to deoxyribose, with a phosphate group between each. Two strands of DNA form a double strand, with links between the bases; C joins to G (with a triple bond), and A joins to T (with a weaker, double bond).

Dominant: see autosomal dominant.

Enzyme: An enzyme is a type of protein that functions as a catalyst — it makes a chemical reaction happen much faster than it otherwise would. Our lives depend on the continuous action of numerous different enzymes.

Exon: the parts of a gene that are translated into protein.

Gene: A gene can be thought of as a set of instructions to the cell, telling it how to make a protein. Genes are long sections of DNA that have a specific structure — regulatory sequences (some of which can be a long way away from the gene itself, some of which are immediately upstream and downstream of the coding part of the gene), exons, and introns. Exons are parts of the gene that are translated into protein. Introns sit in between the exons and are not translated, but they may be transcribed — copied to RNA, which then can have a function including regulating the action of the gene. There are some single-exon genes, which do not have any introns. There are also RNA genes that are transcribed to RNA but not translated to protein.

Genome: All of an organism’s genetic material. Every living organism has a genome.

Genome-wide association study (GWAS): A type of genetic experiment aimed at finding genetic variation that influences a human characteristic. Large numbers of people who are known to be affected by a condition or about whom you know something (such as their blood pressure) are tested for thousands of variations spread across the genome, looking to find a link between a variant and the characteristic you are interested in.

Gonadal mosaicism: This is mosaicism that occurs in the gonads (ovaries or testicles).

Human Genome Project (HGP): The great project to sequence the whole of the human genome.

Intron: The parts of a gene, in between the exons, that are not translated into protein.

Lysosome: A type of organelle that is responsible for waste disposal and recycling in the cell. If any of the enzymes in the lysosome do not work properly, the compound it is supposed to recycle builds up inside the lysosome, with harmful effects.

Mitochondria: The mitochondria have many different functions, but perhaps the most important is metabolising digested food (carbohydrates and fats) to produce a form of energy that the cell can use for its various functions.

Mosaic/mosaicism: If there is a genetic change that is present in some cells but not others, this is mosaicism. This can be at the level of a whole chromosome or at a much smaller scale, including a single base of DNA. In one sense, we are all mosaics, because of the errors that happen whenever a cell divides. For this to be medically important, the mosaicism has to affect a substantial proportion of cells in a given tissue.

Mutation: see variant.

Non-coding: DNA that is not translated into protein is non-coding. See coding for more detail.

Pre-implantation genetic testing (PGT): Also known as pre-implantation genetic diagnosis (PGD). In-vitro fertilisation is used to make embryos that are then tested for genetic conditions. These could be single-gene conditions or chromosomal abnormalities. The idea is to implant only an embryo that is not affected by the condition being tested for.

Protein: Proteins are like verbs in the language of the body: if the cell needs something done, it calls on a protein. Proteins can be machines — the strength in your muscles comes from an interaction between a group of proteins that can turn energy into movement. Proteins can be pumps — the channels in cell membranes are proteins, or protein complexes. Proteins can be factories — the mechanisms for making new proteins include many proteins; the work of the mitochondria in converting food into energy requires the work of many different proteins. Enzymes are proteins. Also, though, proteins can be structural components. The collagens that hold your body together are proteins. Proteins are made up of 20 different amino acids (there’s also a rare 21st amino acid, selenocysteine — see the Notes for chapter 1 for more on this). To make a protein, genes are transcribed (see transcription) to a type of RNA called messenger RNA (mRNA). The introns are cut out (a process called splicing) to make a mature mRNA. This is then translated to protein — structures called ribosomes read the mRNA and add new amino acids to the growing chain. Many proteins then undergo further modification — bits can be carved off each end, chemical changes can be made, and various other substances such as sugars added on — before the protein is fully functional.

Reference sequence: A ‘standard’ sequence of DNA for an organism. The human reference has been updated a number of times as gaps are filled in and errors are corrected. The data on which the human reference sequence is based are from numerous individuals, all anonymous, so that it does not represent any one person. It is not the ‘right’ sequence, but, for the great majority of locations in the genome, it does represent the most common version. If there is a C at a particular place in the reference, it is likely that most people have a C there.

RNA: Ribonucleic acid. Chemically very similar to DNA, with the exceptions that the sugar backbone is ribose rather than deoxyribose, and there is a different base, uracil, in place of thymine. RNA has many different functions and exists in many different forms in the body. These include messenger RNA (mRNA), essential for reading DNA and making protein; ribosomal RNA, which is part of the ribosomes, structures that read the mRNA and build the growing protein; and a raft of signalling molecules of various sizes and functions, from micro-RNA to long non-coding RNA.

Sequence: This word is used both as a noun — the sequence of a section of DNA is the order of the bases — and as a verb. To ‘sequence’ a gene is to read its sequence with the goal of either learning what that usually is, or, in medical applications, to compare it with the reference to see if there are any medically important variants.

Sex chromosomes: The X and Y chromosomes are referred to as the sex chromosomes because of their role in determining whether a person is male or female. The most common arrangement is that girls have two copies of the X chromosome and boys have one X and one Y.

Spinal muscular atrophy (SMA): An autosomal recessive neurological condition that affects the nerves in the spinal cord that control muscle contraction. SMA varies in its severity — the most common form is lethal in infancy if not treated, but there are later-onset forms as well.

Splicing: The process of removing introns from messenger RNA as part of the processing needed to make a mature mRNA that can then be translated. Many genes can have alternative splicing — some exons are variably included or left out — so that the same gene can be responsible for producing multiple different proteins.

Telomere: The protective cap at the end of chromosomes.

Transcription: The copying of DNA into RNA. The resulting messenger RNA is processed, including by splicing out the introns, to make a mature mRNA. This is then translated to make a protein.

Translation: The process of reading messenger RNA and translating its message into protein, by adding on the encoded sequence of amino acids.

Trisomy: literally ‘three bodies’. The state of having three copies of a chromosome instead of the usual two. Trisomy 21 causes Down syndrome.

Variant: Any difference from the reference sequence. This can include variants that have effects on genes, and those that are in between genes. Within a gene, there are also different possible consequences from a variant. For example, it might change the DNA sequence in an exon without changing the resulting protein (because the DNA code has redundancy); it might change the sequence so that a different amino acid is substituted for the usual one; or it might introduce a sequence saying ‘stop’ prematurely. Variants may have different effects on the person in whose genome they are found, as well. Many are harmless (Benign). Some are damaging to the gene in a way that can cause disease (Pathogenic). For some, we are not sure of the possible consequences — these are known as Variants of Uncertain Significance. The word ‘mutation’ technically means the same as variant, but it has long implied that the change is pathogenic; for this reason, the term is falling out of favour. Classification of variants — to decide whether they are relevant to the reason why a test was done — is one of the major challenges in modern genetics, to the extent that there is talk of ‘the $1,000 test with a $10,000 interpretation’.

X-linked: A form of inheritance in which there is a variant in a gene on the X chromosome. This leads to a specific pattern of inheritance. Typically, males are more severely affected by X-linked conditions; females can be affected, usually less severely, but can also have no symptoms at all. If a man with an X-linked condition has children, all his daughters will inherit his X chromosome (that’s why they are girls) and will be carriers (or possibly affected); all of his sons will inherit his Y chromosome (that’s why they are boys) and will not be affected, nor will they be able to pass the condition on. There are some X-linked conditions that virtually only affect girls, because the effects on a male with no functioning copy of the gene are so severe that no males affected in this way are born.