The Boy Who Wasn't Short

by Kirk, Edwin;

  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 tha
t 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.

  Acknowledgements

  I owe debts of gratitude to many different people for their roles in making this book possible. The chance to write the book came along in a year that was already set to be the busiest of my life, and writing it has often kept me away from my family. I’m deeply grateful to my wife, Sue, and my children, Seamus, Yasmin, and Finn, for their love and support. Every seven years, Sue — but always with you.

  The chain of events that led to the writing of the book began with my friend Denny Mrsnik, who introduced me to my agent, Tara Wynne. Tara and Caitlan Cooper-Trent, both from Curtis Brown, have been wonderful to work with. Tara critiqued early chapters and provided valuable guidance, acting as literary coach as much as agent. She took the book to Scribe, and she and Caitlan have been working tirelessly to find other opportunities for me. I hope this will prove to be the start of a long and fruitful partnership.

  I am very grateful to all at Scribe. I’d particularly like to thank Henry Rosenbloom (Scribe’s founder and publisher) and his editorial team, for taking a chance on a novice writer. My editor, David Golding, has been brilliant. I have David to thank for the title of the book, and for countless improvements throughout the text. David combines great attention to detail with an ability to keep the whole in mind; it has been a privilege working with him. Laura Thomas designed the wonderful cover — I find myself liking it more and more every time I look at it. Mick Pilkington, design and production manager, played a pivotal role in bringing together all the elements of the book: without his work, the physical object you hold in your hands, if you have a physical copy, would not exist. And without the efforts of Chris Grierson from marketing, and Cora Roberts from the publicity department at Scribe, and their teams, you probably never would have heard of the book at all.

  I showed drafts of all or part of the manuscript to a number of people. Denny Mrsnik, Seamus Kirk, Sarah Righetti, and Michael Buckley read the whole thing and made numerous helpful comments; Seamus also gave me the quote that starts chapter 1. Others who read sections of the book and suggested improvements, or who made helpful general comments about the book as a whole, include (in no particular order) Colin Nichols, Alan Ma, Jacqui Russell, Lisa Bristowe, Nigel Laing, Martin Delatycki, David Thorburn, Michelle Farrar, Robert Mitchell, Eileen Forbes, Rachael and Jonathan Casella, and Richard Harvey. Tony Roscioli gave me helpful and timely advice about protecting patient confidentiality. Michael and Colin both found scientific errors and corrected them. I have tried hard to make sure that no others remain in the book, but, if there are errors, the fault is entirely my own and not that of any of those who helped me. Michelle Farrar gave me a helpful tutorial on muscle satellite cells, and Finn Kirk pointed out that extracting DNA from strawberries is easier and works better than extracting it from onions, leading to a change of recipe in chapter 2. Professors Peter Campbell and Philip Jones kindly provided the image from their paper used in chapter 3.

  At the same time that I was writing the book, the preparations for starting recruitment of couples for Mackenzie’s Mission were underway, and I’d like to take this opportunity to thank the many people who have contributed to the project so far. There are more than 80 people who are investigators contributing to the project’s committees, or who have other key roles, and dozens more without whose work we could not hope to succeed. I’m especially grateful to the executive team — my fellow leads, Martin Delatycki and Nigel Laing; Jade Caruana, our program coordinator; and Tiffany Boughtwood, manager of Australian Genomics. The project is being delivered through the infrastructure of Australian Genomics, which is led by Kathryn North — who is also a member of our steering committee. Without Rachael and Jonathan Casella, none of this would have been possible, and Rachael has been a valued contributor to the project in many ways, including as a member of the steering committee. In NSW, I’d like to particularly mention Sarah Righetti, our administrator, without whom 2019 would have completely overwhelmed me; Kirsten Boggs, Lucinda Freeman, and Kristine Barlow-Stewart, our genetic counsellors; and all of the team at the NSW Health Pathology Randwick Genomics Laboratory, but especially Corrina Cliffe, Bianca Rodrigues, Natalia Smietanka, Guus Teunisse, Ying Zhu, Janice Fletcher, Tony Roscioli, and Michael Buckley. Thank you all.

  Notes

  This section is for additional detail, sources, and references, although referencing is not intended to be at the level of a scientific paper.

  Preface

  Genetics has taken me to some unexpected places: This isn’t intended to be a book about me, so I never quite found room to expand on this in the main text.

  The room in the basement full of mice was the mouse facility at the University of Sydney’s School of Veterinary Science, where I spent a lot of time while I was working on my PhD.

  I went to Pakistan while taking part in production of a television program for the Discovery channel. This was not a high watermark for television, so I suggest you don’t seek it out online. But this did give me the chance to spend time in Lahore, a rare privilege. While there, I had the chance to visit the magnificent Badshahi Mosque, a masterpiece of Mughal architecture and probably the most beautiful building I’ve ever seen.

  At the Badshahi Mosque I was just a tourist, but I visited a mosque in Western Sydney for quite a different reason. The latter visit was part of preparations for a study of carrier screening in couples who are related to one another (mentioned in chapter 11). There are many parts of the world where cousin marriages (mainly, although in some places uncle–niece marriages also occur) are culturally favoured, including much of the Middle East. While the practice is not specifically linked to religion — cousin marriages are common among Lebanese Christians, for instance — Islam predominates in those regions, and it was important to us to consult with relevant religious and other community leaders before starting the study. My friend and collaborator Kristine Barlow-Stewart and I visited one large mosque together, among other meetings we had in preparation for the study. I visited another without Kris. At that mosque, I met an imam who had two PhDs — possibly the most highly educated person I’ve ever met, and a kind and attentive host. Having done one PhD myself, I found the idea of someone voluntarily undertaking a second a little hard to grapple with. After our meeting, I was offered a tour of the mosque. The young man in a hoodie who was tasked with showing me around greeted me with a hopeful expression. ‘Are you a convert?’ he asked.

  1. Easier than you think

  DNA is
a chemical: Okay, here’s some chemical detail, if you have a stomach for that sort of thing. The four nucleobases, or bases, that make up DNA are adenine, cytosine, guanine, and thymine (A, C, G, T). DNA is short for ‘deoxyribonucleic acid’. Each base of DNA is either a carbon ring (C, T) or double ring (A, G) and is attached to a sugar called deoxyribose and a phosphate; together, the base plus sugar plus phosphate are referred to as a nucleotide. Each nucleotide joins from sugar to phosphate in a long chain; the double helix forms when the rings and double rings of the bases are attracted to each other by hydrogen bonds. C sticks to G with three bonds; A sticks to T with two — so where there are lots of Cs and Gs, the double helix is tighter and harder to separate. There’s another important base, uracil, that stands in for thymine in RNA (ribonucleic acid — which has a slightly different sugar backbone). That sounds complicated but it’s all just detail. ‘DNA is a chemical that contains information … written in an alphabet with only four letters: A, C, G, T’ covers the main points.

  the language of DNA has only 21 words: All right — there is just a little more to it than that. For a start, there are actually 64 ways of spelling those 21 words (four possibilities for the first letter, times four for the second, times four for the third). This means that there are alternative ways of spelling most of the words — as if kat were a routinely used alternative way of spelling cat. For nine of the amino acids, there are two possible DNA codes; for one, there are three; for eight, there are four. There are just two amino acids — methionine and tryptophan — with unique DNA spellings. There are three ways of coding for ‘stop’ — TAA, TAG, and TGA all mean this. ATG spells methionine, but it also codes for ‘start’. And there is a 21st word, selenocysteine. The amino acid cysteine contains a sulphur, but, in selenocysteine, this is replaced by a selenium. If there’s enough selenium about (i.e. you aren’t deficient in it), then TGA can mean ‘put a selenocysteine here’ instead of ‘stop’. There are about 50 human proteins that contain selenocysteine, a tiny but important fraction of the whole. Selenocysteine was only discovered in the 1970s, long after the other amino acids, by the American biochemist Thressa Stadtman.