One of the main reasons we seek to understand genetics is so that we can use it to solve problems, not least problems with the human body. Many inherited disorders that cause great suffering are caused by genes, and could perhaps also be cured with genetics. The likes of sickle-cell anaemia, haemophilia and Huntington’s disease are caused by a single gene, while others are the product of larger errors at the level of the chromosome. Many diseases have genetic components as well, and the future of medicine is likely to be focused on tailoring treatments individually, according to the patient’s genetic makeup.
Human genetics is best expressed using the ‘karyotype’. This is a snapshot of all of a person’s chromosomes as they are coiled up ready for a cell division. There are 46 in all: one pair of sex chromosomes and 22 pairs of autosomes. This is the first place doctors search when diagnosing genetic disorders, looking for mismatched chromosomes that indicate something is awry.
The human karyotype is a representation of 46 chromosomes in 23 pairs.
Dubbed ‘one of the great feats of exploration in history – an inward voyage of discovery rather than an outward exploration of the planet or the cosmos’, the Human Genome Project was 20 years in the making. In 2003, it succeeded in reading every piece of human DNA, sequencing the nucleotide bases in the sense strands of the haploid human genome (that’s 23 chromosomes, not the full 46). The Human Genome Project got most of its source material from an unnamed man from Buffalo, New York, with a few samples from other donors. The result is 25 lists of nucleotides: 22 autosomes (non-sex chromosomes), both the X and the Y chromosomes, and the tiny strand of mitochondrial DNA. All together, they amount to roughly 3 billion characters, but what does that really add up to? The data amassed by the Human Genome Project is unique to its donors – it is not a blueprint for all humans. But it still provides a reference for identifying those parts of the genome that are coding DNA and those which are ‘junk’. In this way, the real exploration of the human genome has only just begun.
Every person has one of four blood types: A, AB, B or O. They are an inherited trait, and the genes involved are an object lesson in Mendelian genetics. The types relate to antigens, or marker chemicals, that appear on the surface of red blood cells. There are also antibodies that roam the blood stream in search of aliens – things with different antigens to the blood. So a person with A blood, has A antigens on their cells and B antibodies in the blood stream. These antibodies lock onto any cells with the B antigen, alerting the immune system.
Blood types are controlled by the genes A, B and O. The genotypes AA or AO result in the A blood type; B blood is from BB or BO genotype. Inheriting both an A and a B allele produces the AB blood group. These blood cells have both A and B antigens, and there are no antibodies. The genotype OO results in the O blood type, where the cells have no antigens and the blood contains both antibodies. This means O blood can enter any system undetected, while AB blood can accept all other blood types.
HLA stands for ‘human leukocyte antigens’, relating to a set of genes that code for the antigens, or chemical markers, that act as an identity system for the body’s cells. The HLA genes produce about a dozen antigens that appear on every cell – some are more important than others. The immune system ignores the cells that have these markers, and attacks anything that has an alien antigen. This is how pathogens, or infectious agents, are generally identified for removal. (Some pathogens and parasites are able to adopt the HLA of their host and so stay hidden.) An individual’s HLA types can be ascertained using antibody tests in the lab. This is how donor organs are matched to recipients for transplant. HLA types are also linked to ethnic groups, and are useful in research into human migration. Most of the HLA genes are clustered on chromosome 6. Some of them are associated with inherited disease such as coeliac disease and types of arthritis. This is because the disease genes sit right next to the HLA ones on the chromosome and are likely to be inherited together.
In the 19th century, one of the goals of the emerging field of anthropology (the study of humans) was to put our species into its biological context. One of the results was the notion of racial groups, frequently simplified into a few major races such as australoid (from Australia), mongoloid (East Asia and Americas), caucasoid (Europe and South Asia) and negroid (Africa). Whatever its origin, this kind of thinking was frequently deployed as a way of proving the superiority of Europeans. Attempts were made to link inherited phenotypes such as skin colour, hair type and skull shape to intelligence, personality and even morality. All of them failed, but that did not stop pseudoscientific opinions taking hold – the impact of which linger to this day. In population genetics, the term ‘race’ is seldom used. Instead a gradual change in the phenotype of a population across a wide region is called a cline, and this better reflects the many phenotypic differences of humans. Nevertheless, the differences between all 7.3 billion of us comes down to just 0.5 per cent of our DNA.
It is not unusual for plants, especially crops, such as wheat and tomatoes, to carry multiple sets of chromosomes over and above the normal two. This phenomenon is called polyploidy, and in plants it results in larger plant bodies – hence its appearance in crops. Some animals are polyploid with no ill effects – a few fish species have as many as 400 chromosomes in every cell. Polyploidy is often linked to parthenogenisis (see here) in which a female produces young without needing to mate. This carries a higher chance of cell division errors placing multiple sets of chromosomes into a zygote. A similar process can happen in humans, most commonly when an ovum (egg cell) is diploid and already contains 46 chromosomes. The sperm adds another 23 at fertilization, resulting in a ‘triploid’ (three-set) zygote with 69 chromosomes. It is estimated that 2 per cent of all human conceptions result in triploidy – plus a few more producing ‘tetraploidy’. The great majority will result in miscarriage, with 15 per cent of spontaneous abortions being caused by this single factor alone.
Named after John Down, the British doctor who described it in the 1860s, Down’s syndrome is the result of a type of chromosomal disorder called aneuploidy. This is when there is an abnormal number of chromosomes in the body cells. In the case of Down’s syndrome, the cells are ‘trisomy 21’, meaning they have three versions of chromosome 21, rather than the normal two. As a result of this extra genetic material, people with trisomy 21 tend to be shorter than average, have distinctive facial features and usually suffer from heart problems. They also tend to have an adult IQ of around 50, in line with the average nine-year-old, although this ranges widely.
Another aneuploidy disorder is Turner syndrome, where the cell has only one X chromosome. Sufferers are female, shorter than average and have fertility problems. In Klinefelter syndrome, meanwhile, a male has the genotype XXY. The extra X makes him grow very tall and develop a mix of male and female characteristics.
A copy-number variation (CNV) is a common chromosomal abnormality. It arises during the replication of a chromosome and results in a sizable section of DNA being deleted or duplicated. As a result, the daughter chromosome has a different number of genes – often multiple copies of the same ones – than in the parent chromosome. Anywhere from one thousand to several million bases can be involved in a CNV. It is estimated that 13 per cent of the variation among human genomes is due to this kind of chromosomal mutation. (Most of the rest comes from point mutations where a single nucleotide base is altered.)
CNVs among the human population were discovered by the Human Genome Project. Stable CNVs, which have little or no impact on the phenotype, are passed on down the generations. Large CNVs can cause infertility, because they produce a mismatch in length of homologous pairs, and this reduces the success rate of meiotic divisions (see here).
One of the advantages of having diploid cells, equipped with two sets of every gene, is that if one gene proves faulty there is another to override its effects. The 22 non-sex chromosomes or ‘automsomes’ form matching pairs, but the 23rd pair, made up of the sex chromosomes, can be unequal. Females have two Xs, while all males have an X and a Y. The Y chromosome is much smaller than the X, with 59 million base pairings compared to the X’s 153 million. As a result, there are genes present on the X that are not matched on the Y. Therefore, when a deleterious gene appears on an X chromosome in a female cell, the opposing X can mask its effects. Yet that same ‘X-linked’ gene will be free to express itself in a male cell, since the Y offers no such defence. As a result, several inherited disorders are X-linked and almost exclusive to males. These include colour blindness, haemophilia and Duchenne muscular dystrophy. Females are generally carriers of these diseased genes, but will only suffer themselves if they inherit two X chromosomes carrying the faulty gene.
Tsarevich Alexei Romanov, heir to the Russian throne (second from right), suffered from haemophilia, an X-linked blood disease inherited from his great-grandmother Queen Victoria, who was a carrier.
The uncontrolled growth of a body tissue, generally resulting in a tumour, is known as a cancer. The tumour may have far-reaching effects by spreading through the body, disrupting its normal workings and eventually overwhelming a vital organ or pushing the body’s immune system beyond its limit.
Cancer is not one disease but many different ones – around 200 in total. They have just as many causes, including exposure to a carcinogenic substance, ionizing radiation, certain infections and also genetics. In most cases it is an accumulation of these factors that trigger development of a cancer, but all cancers begin with a change in certain genes, known as the oncogenes. These genes are involved in rapid cell divisions and are normally switched off after the embryonic stage. However, if they are switched on again, they override the process of controlled cell death that maintains body tissue at a fixed size. The result is uncontrolled growth in a certain part of the body, leading to a tumour.
Every cancer begins with the uncontrolled growth of a primary tumor, arising from a single abnormal cell. Changes in the tumor cells can lead to metastasis, where new, genetically different tumors spread through the body.
Everyone is familiar with viruses – we have all been intimately acquainted with them at some point in our lives when suffering during a viral disease, such as the common cold or chickenpox. But few appreciate that by most measures, a virus is not really a living thing. The best way to understand it is as parasitic DNA.
The virus ‘body’ is made up of a coil of DNA (or sometimes RNA) surrounded by a protective protein coat. It is parasitic because, unable to replicate its own DNA, it hijacks the replication system of a cell. The protein coat attaches to the membrane of the cell and makes a channel through it for the DNA to enter. The DNA is then taken to the nucleus and causes the cell to make copies of it and its proteins continuously – until the cell is so full that it bursts, releasing new viruses to infect new hosts. This process is what kills cells and creates creates illness. Make no mistake, viruses are no genetic sideshow; a single cup of seawater contains more viruses than there are humans on Earth, each one evolved to parasitise a specific genome—and mercifully few targeted at us.
Derived from a contraction of the terms ‘protein’ and ‘infection’, a prion is a disease-causing agent which, like a virus, is non-living. However, unlike viruses and all other infectious agents, prions contain no genetic material. Instead, they are malformed proteins. They originate as proteins synthesized in the normal way within the cell, and have a structure that makes them of use in metabolism. However, many proteins are able to refold into alternative shapes, of no metabolic value. Prions are a mercifully rare subgroup of proteins that become self-propagating once they become malformed. The misfolded protein acts as a template or mould that causes healthy proteins to take on the same malign shape. Now there are two, and the process continues, creating an exponential buildup of bad proteins. The proteins cluster together to form fibres called amyloids that damage tissue. Prions were not discovered until the 1980s: to date all known prion diseases, such as Creutzfeldt-Jakob Disease, attack the brain or nervous system, have no cure and are invariably fatal.
We have all been drawn into the nature versus nurture debate at some point: does our personality arise from an innate inheritance or is it moulded by our experiences? Most modern thinkers would agree with the teaching of 17th-century philosopher John Locke, that the mind of a newborn is empty of knowledge, a ‘tabula rasa’, or clean slate. The things we then experience fill our memory and mould our attitudes as we grow, but do genetics play a role? No one suggests that states of mind and social attitudes are inherited. However, the fabric and function of the brain that creates those states probably is.
In the United States, defence lawyers can argue that the structure of their client’s brain reveals a cognitive deficiency to explain and excuse a crime. However, studies of brain development during pregnancy and after trauma show that it is ‘plastic’ and alters its functional map throughout life. This would suggest that in most cases, nurture tends to dominate nature.
Meaning something like ‘well born’, eugenics is now seen as embodying the darker side of human genetics, a theory that the human species could be improved by breeding out unwanted personality traits in favour of intelligence and other desirable qualities. The idea was the brainchild of Francis Galton, a cousin of Darwin. Being a Victorian gentleman, he assumed that his kind was a superior breed to the rest of humanity, and that the mechanisms of inheritance and selection outlined by Darwin and others could be used to make everyone ‘better’ – more like him.
But how to identify inheritable traits in the first place? Galton was aware of the nature vs nurture debate (indeed, he coined the phrase), and from the 1880s he attempted to link physical features to intellectual faculties. Galton found no correlations, but the idea of eugenics persisted. Ultimately, it was behind widespread efforts to sterilize the mentally ill (including one Swedish programme that continued into the 1970s), and also found a hideous outlet in the Nazi Holocaust.
Francis Galton used himself as a benchmark in the search for a link between body shape and intelligence.
There has long been an assumption that intelligence is inherited. An early idea was that brain and skull size correlated to intelligence. All attempts to prove this failed, not least because there was no way of measuring intelligence. In the 1890s, French neuroscientist Alfred Binet took a new approach by devising a test for intelligence, based on problem solving while avoiding the need for advanced reading and writing skills. Binet’s test questions got progressively harder, with each one designed to be answerable by 50 per cent of a specific age group, rising with each question. The place in the test where a person faltered showed their ‘mental age’. From 1916, a similar test that produced an average score of 100 became known as the IQ test, measuring a person’s ‘intelligence quotient’. IQ tests are still around today, although we seem to be getting cleverer: the tests must be regularly upgraded to keep the average score at 100. IQ scores and academic attainment run in families, suggesting they may have a genetic factor. But, the mechanisms by which hypothetical ‘genes for intelligence’ act remain a mystery.
The most powerful research tool into the genetics of personality and intellect is twin research. Identical twins are physically and genetically the same in every way – but while their nature is a match, what about their nurture? The holy grail of twin research is to study identical twins that have been separated soon after birth. The twin’s nature might make them grow up into adults that act the same and share the same likes and dislikes. But if the way they were nurtured is a major factor, then these identical twins need not share a similar personality. Such research offers the prospect of discovering ‘a gene for’ all kinds of mental traits.
In practice, separated twins frequently present similar personalities, and statistical analysis suggests about half of that similarity is due to genetics. Isolating an actual gene that codes for personality has proved impossible to date, but a better understanding of the way a brain develops under various stimuli may eventually point the way to the genetic component.
The term epi- means ‘on top of’, and an epigenetic process is one that impacts on the expression of a gene due to some environmental factor. Multigenerational studies have recently made a rather startling discovery: epigenetic effects seem to be passed on along with genes, at least for one or two generations.
As well as a genome, every cell carries an epigenome – an array of helper chemicals studding the chromosomes. Some helpers coil up unused genes to save space (for example, blood cell genes inside a bone cell). Others unravel sections that are in constant use. Unlike the genome, the epigenome changes in response to environmental stimuli, and researchers are racing to find out more, acting on the hunch that this process is what links diseases such as cancer with poor diet and other bad health choices. Further to this, evidence is growing that the epigenome – or at least some of it – can pass to the offspring, and even to grandchildren. That would mean our genetic inheritance is somewhat pliable, and not set in stone.
DNA is bound together by a protein core in the chromosome. Proteins and other molecules form the epigenome, which presents certain genes for use and hides others away.
The first evidence of epigenetic inheritance emerged from the Dutch Hunger Winter, a famine caused by a Nazi blockade in the winter of 1944–45. It resulted in thousands of deaths from starvation, but after the war it presented a unique opportunity to study the effects of malnutrition. Babies conceived before the famine had low birth weights; they lacked nutrition in the final stages of development and so did not grow much, remaining small throughout their lives. Babies conceived during the famine, however, had normal birth weights: their early development was during the famine, but the final trimester occurred after it, and their growth caught up. In later life, however, this second group were found likely to be obese and suffer mental illness – and surprisingly, so were their children. The theory is that such problems are caused by an epigenome, created by the famine, that formed in the mother, the foetus and the foetus’s germ line (which would eventually produce its own gametes). The question remains – can the epigenome pass further, beyond these generations?
Are genes the only things that are subject to natural selection? One proposal suggests not. Memes, a unit of knowledge or memory, can pass from mind to mind replicating in the same way as a gene would do. For example, the meme for applause is a highly successful one. We learn, or inherit, this idea from others, and pass it on in the same way. Clapping has remained remarkably stable for years and is used across most cultures. However, there are ‘mutant’ forms, where applauders stamp or bang a table. These mutants have taken root in habitats where they fit better than clapping. Some memes are less successful, only spreading among certain communities or being completely forgotten – effectively going extinct. Memetics seeks to use genetic motifs to investigate the nature of ideas, but it eventually fails. While our definition of the meme equates to that of the phenotypic gene, it does not match the genotypic one, a physical strand of DNA. Ideas are not stored by the brain as discrete memes, but are recalled by associating a complex and distributed set of different memories.
