Principles of Inheritance and Variation: Class 12 Biology · Chapter 4

Farmers who grow hybrid rice or hybrid maize buy fresh seed every season. If they save grain from their own crop and sow it, the next field is a mixed bag. Some plants are tall and some short, some early and some late, most of them yielding less. Seed saved from a traditional variety, by contrast, comes up looking just like its parents year after year. Why should seed from one field breed true while seed from another scatters? By the end of this chapter you will be able to explain it.

The science behind such questions is genetics (आनुवंशिकी). It asks two linked questions. How are characters handed from parents to offspring? That handing on is inheritance (वंशागति). And why are offspring never exact copies of their parents, or of each other? Those differences are variation (विविधता).

Selective breeding is far older than genetics. Traditional crop varieties, and India's Gir and Tharparkar cattle or Murrah buffaloes, were created over thousands of years by people who chose which plants and animals to breed from, without knowing why the choosing worked. The first rules that could predict the next generation came out of a monastery garden in the 1860s.

4.1 Mendel's Laws of Inheritance

Gregor Mendel, a monk in Brno (now in the Czech Republic), spent the seven years from 1856 to 1863 crossing garden pea plants and counting their offspring. Three habits set his work apart. He followed one clear-cut character at a time instead of the plant as a whole. He raised and scored thousands of plants, so that chance effects evened out. And he reasoned from the counts mathematically, testing each idea by predicting the next generation and then growing it. Numbers and probability had hardly ever been used to settle a question in biology before.

The pea itself helped him in several ways:

• Its flowers normally pollinate themselves inside closed petals, so a line kept on its own stays pure for generations.
• The same flowers can be opened and pollinated by hand whenever the experimenter wants a particular cross.
• A generation grows in a single season, and every plant sets many seeds to count.
• Many of its characters come in two sharply different forms with nothing in between, so every plant can be scored without argument.

Before crossing anything, Mendel made sure each starting line was true-breeding: generation after generation of self-pollination had left it producing offspring exactly like the parents for the character he studied. Fourteen such lines, matched in seven pairs, were his material. The partners in a pair were alike except for one character. The seven characters were seed shape (round or wrinkled), seed colour (yellow or green), flower colour (violet or white), flower position (along the stem or bunched at its tip), pod shape (inflated or constricted), pod colour (green or yellow) and stem length (tall or dwarf).

To cross two lines, Mendel had to stop the chosen seed parent from fertilising itself and then give it pollen from exactly one other plant. Fig. 4.1 shows the procedure. The anthers are removed from a flower bud before they shed pollen, a step called emasculation, and the flower is covered with a bag so that no stray pollen reaches it. When the stigma is ready, pollen from the chosen pollen parent is dusted on, the bag goes back on, and the seeds that form are the first generation of the cross.

4.2 Inheritance of One Gene

Take one of Mendel's character pairs, pod colour. One true-breeding line has green pods, the other yellow. Cross them, and the seeds grow into the first filial generation, the ${\mathrm{F}}_1$ (from the Latin for son or daughter). Every ${\mathrm{F}}_1$ plant has green pods. Yellow has not been diluted into a yellowish green; it has vanished from view.

Now let the ${\mathrm{F}}_1$ plants pollinate themselves. In the second filial generation, ${\mathrm{F}}_2$, yellow pods are back, exactly as yellow as in the original parent. Mendel counted 428 green-podded and 152 yellow-podded ${\mathrm{F}}_2$ plants, close to three green for every yellow. His other six characters behaved the same way (Table 4.1): one form alone in the ${\mathrm{F}}_1$, both forms in the ${\mathrm{F}}_2$ in about a 3 : 1 ratio, and never a blend.

Mendel's explanation was bold for its time. Every plant, he argued, carries two hereditary particles for each character, which he called factors; a gamete takes just one of them, and the particles never mix or change. Today we call his factors genes. A gene is a stretch of DNA (Chapter 5) carrying the instructions behind a character, and it can exist in more than one version. The versions of one gene are its alleles (युग्मविकल्पी): pod colour has an allele for green and an allele for yellow.

Geneticists give each gene one letter. A capital stands for the allele that shows in the ${\mathrm{F}}_1$ and the lower-case form of the same letter for its partner. So G (green) and g (yellow) are instantly recognisable as alleles of one gene. Each plant carries two copies of the gene, so three combinations exist: GG, Gg and gg. A plant with two identical alleles, GG or gg, is homozygous; a plant with two different alleles, Gg, is heterozygous.

The letters describe a plant's genotype, its genetic make-up for the character. What we see, a green or a yellow pod, is its phenotype. GG and Gg plants share a phenotype but differ in genotype, because in Gg the G allele masks g. G is therefore dominant (प्रभावी) and g is recessive (अप्रभावी). The ${\mathrm{F}}_1$ plants are heterozygous for one character, so they are monohybrids, and GG × gg is a monohybrid cross.

Why does yellow come back? Think of the alleles as separate tokens. Meiosis parts the two alleles of a pair, so every gamete holds exactly one token for each gene. The green parent could hand on only G and the yellow parent only g, so each ${\mathrm{F}}_1$ plant holds one of each and looks green. Inside it, though, the g token is intact. When the ${\mathrm{F}}_1$ makes gametes, half receive G and half g, purely by chance, in pollen and eggs alike, and a g pollen grain meeting a g egg rebuilds a yellow-podded plant.

To keep track of every possible meeting of gametes, geneticists use a chequerboard introduced by Reginald C. Punnett of Cambridge, the Punnett square. List the egg types down one side and the pollen types across the top. The box where a row and a column cross holds the offspring of that particular egg and pollen grain. Because every meeting is equally likely, so is every box. Fig. 4.2 follows the cross from the parents to the ${\mathrm{F}}_2$.

Count the boxes: one GG, two Gg and one gg. The genotypic ratio of the ${\mathrm{F}}_2$ is therefore 1 : 2 : 1. Since GG and Gg both give green pods, the phenotypic ratio is 3 green : 1 yellow. You can reach the same answer algebraically: the ${\mathrm{F}}_1$ gametes carry G and g with probability 1/2 each, and squaring that sum lists every zygote with its probability, just like a binomial expansion.

Mendel carried some lines on for further generations. ${\mathrm{F}}_2$ plants with yellow pods, selfed, never gave anything but yellow-podded offspring, so they had to be homozygous, gg. The green-podded ${\mathrm{F}}_2$ plants were less predictable (Example).

A green pod tells you that a plant has at least one G, but not whether it is GG or Gg. The trick is to mate it with a homozygous recessive plant. Such a test cross (परीक्षार्थ संकरण) works because the recessive partner can only contribute recessive alleles, which hide nothing: whichever allele the tested plant passes on decides each offspring's phenotype directly.

Fig. 4.4 works through a test cross for flower position, where axial flowers (A: flowers along the stem) are dominant over terminal flowers (a: flowers bunched at the tip).

If every offspring is axial, the tested plant was almost certainly AA; if about half are terminal, it was Aa. Notice the asymmetry: a single terminal offspring proves the parent carries a, but a run of axial offspring can only make AA more and more likely (Example).

4.2.1 Law of Dominance

From his crosses involving one character, Mendel drew two general rules. Today they are called the law of dominance and the law of segregation.

It is why a monohybrid ${\mathrm{F}}_1$ looks like only one of its parents; combined with segregation, it also produces the 3 : 1 of the ${\mathrm{F}}_2$.

4.2.2 Law of Segregation

Notice what the law predicts for gametes. GG and gg plants make one kind each, while a Gg plant makes G and g gametes in a 1 : 1 ratio, exactly what a test cross reveals. The strongest evidence for the law is the yellow ${\mathrm{F}}_2$ pod, as yellow as its grandparent's after a generation in hiding. Because each gamete carries a single, unmixed allele, the law is also called the law of purity of gametes.

4.2.2.1 Incomplete Dominance

Mendel's seven characters all showed complete dominance, but many characters in other organisms do not. In the four o'clock plant, Mirabilis jalapa (gulbas in many Indian gardens, named for flowers that open in the late afternoon), crossing a true-breeding red-flowered line with a true-breeding white-flowered line gives an ${\mathrm{F}}_1$ with pink flowers. The hybrid lies between its parents. This is incomplete dominance (अपूर्ण प्रभाविता): neither allele fully masks the other.

Self the pink ${\mathrm{F}}_1$ and the ${\mathrm{F}}_2$ contains red, pink and white plants (Table 4.2). Compare this with a pea cross. The Punnett square is identical, 1 RR : 2 Rr : 1 rr. Each genotype now has a look of its own, so the phenotypes come out 1 : 2 : 1 instead of 3 : 1. Red and white also reappear exactly as they were in the grandparents, so the alleles themselves never blended; only their effects combine in the hybrid.

What makes an allele dominant?

Why should one allele hide another? The answer lies in what genes make. Picture a flower whose violet pigment is built by a single enzyme, coded by one gene with two alleles. V carries working instructions, while v is a damaged copy that yields a useless enzyme or none at all (Fig. 4.5). A VV plant makes plenty of pigment. A Vv plant makes less enzyme, yet enough to colour every petal fully, so it looks exactly like VV: V is dominant. Only a vv plant, with no working copy, has white flowers.

This explains a general pattern: recessive alleles very often turn out to be non-working versions of a gene, and one working copy is usually enough. Not every altered allele is broken, though. Some still make an enzyme that works normally or almost normally; such an allele is equivalent to the original and changes nothing we can see, and pairs like this are common. And when a phenotype depends on the amount of product, as in the four o'clock plant (Section 4.2.2.1), one working copy gives only half the pigment and the heterozygote is intermediate.

4.2.2.2 Co-dominance

Before a blood transfusion, a hospital checks which of four groups, A, B, AB or O, the patient belongs to. The groups differ in the short sugar chains that decorate the surface of the red blood cells (Fig. 4.6). Group A cells carry sugar A, group B cells sugar B, AB cells both and O cells neither.

One gene, I, decides the sugar. In the human population it comes in three alleles: $I^A$ builds sugar A, $I^B$ builds sugar B, and $i$ builds nothing. Look first at an $I^A{I}^B$ person. Neither allele masks the other: both sugars appear, each in full. This is co-dominance (सहप्रभाविता): the heterozygote shows the phenotypes of both alleles side by side, unlike the in-between hybrid of incomplete dominance or the one-sided hybrid of complete dominance.

The allele $i$ behaves differently. Because it adds no sugar, an $I^{A}i$ person cannot be told apart from an $I^A{I}^A$ person, so $I^A$ and $I^B$ are each dominant over $i$. Three alleles can pair up in six ways, giving six genotypes and four blood groups (Table 4.3).

Notice that the I gene has three alleles, although each of us carries only two. A gene with more than two alleles in a population is said to have multiple alleles; you can discover them only by surveying many individuals, never by studying one. Coat colour in rabbits is another case: four alleles of one gene give full-coloured, chinchilla (silvery grey), Himalayan (white with dark ears, nose and paws) and albino coats.

4.3 Inheritance of Two Genes

Next Mendel followed two characters at once. Our version of his experiment uses flower position and pod colour. One true-breeding parent has axial flowers and green pods (AAGG); the other has terminal flowers and yellow pods (aagg). Each parent makes only one kind of gamete, AG or ag, so every ${\mathrm{F}}_1$ plant is AaGg, with axial flowers and green pods. So far nothing is surprising: each character behaves as it did on its own. Heterozygous for two genes, the ${\mathrm{F}}_1$ is a dihybrid, and the cross is a dihybrid cross.

Now let the ${\mathrm{F}}_1$ pollinate itself. Look at one character at a time in the ${\mathrm{F}}_2$ and nothing new appears. Three quarters of the plants are axial and one quarter terminal, and, separately, three quarters have green pods and one quarter yellow. Each character still splits 3 : 1, just as in a monohybrid cross. The new question is how the two characters combine.

4.3.1 Law of Independent Assortment

The ${\mathrm{F}}_2$ has four phenotypes: axial green, axial yellow, terminal green and terminal yellow, in the ratio 9 : 3 : 3 : 1. Two of them, axial yellow and terminal green, are new combinations that neither original parent showed. The ratio is just the two 3 : 1 ratios multiplied together, which is what you expect if each character is inherited without reference to the other:

(In Section 4.3.3 we shall see that this holds for genes on different chromosomes, but not for genes close together on the same chromosome.)

Think of gamete formation in an AaGg plant as two independent coin tosses: one decides A or a, the other G or g. Two coins give four equally likely outcomes, so the plant makes AG, Ag, aG and ag gametes, a quarter each, among its eggs and its pollen alike. Placing them along both sides of a Punnett square gives a 4 × 4 grid of 16 equally likely boxes (Fig. 4.7).

The 16 boxes hold only nine different genotypes, which fall into four phenotypes. Try sorting them yourself before checking Table 4.4. The genotypic ratio is not 9 : 3 : 3 : 1. It is 1 : 2 : 1 : 2 : 4 : 2 : 1 : 2 : 1, which is (1 : 2 : 1) × (1 : 2 : 1).

4.3.2 Chromosomal Theory of Inheritance

Mendel presented his results in 1865 and they were printed in 1866, yet for more than thirty years hardly anyone built on them. Historians point to several reasons:

• No physical basis. Nobody, Mendel included, could point to a factor in the cell or say what it was made of.
• A strange method. Biologists of the day described and compared; few were ready to accept conclusions drawn from ratios and probability.
• Blending seemed obvious. Most variation in nature, in height, weight or colour, is continuous, which looked like evidence that parental characters mix, not that discrete factors are passed on.
• An obscure journal. His paper appeared in the proceedings of a small local society and was rarely read.

Meanwhile cell biologists, armed with better lenses and new dyes, had been watching nuclei divide. They saw thread-like bodies that took up stain strongly, hence the name chromosomes, 'coloured bodies'; each doubled before a division, and by 1902 the way they move in meiosis was understood. In 1900 three botanists working separately, Hugo de Vries, Carl Correns and Erich von Tschermak, had reached Mendel's ratios in their own crosses and then found his forgotten paper. The two lines of work were about to meet.

They met in 1902, when Walter Sutton in the United States and Theodor Boveri in Germany pointed out that chromosomes in meiosis behave exactly as Mendel's factors must (the comparison below). Their proposal, which Sutton set out as the chromosomal theory of inheritance, is simple to state: Mendel's factors are parts of chromosomes, and segregation and independent assortment are what chromosomes do in meiosis. Body cells hold chromosomes in homologous pairs, one member of each pair from each parent. The two alleles of a gene sit at the same position, the gene's locus, on the two members of a pair.

Fig. 4.9 shows how this explains independent assortment. Suppose gene A lies on one pair of chromosomes and gene G on another. At metaphase I each pair lines up at the middle of the cell, one homologue facing each pole. Which homologue faces which pole is settled separately for each pair, like two coins tossed independently. One alignment sends A and G to one pole and a and g to the other; the other, equally likely, alignment sends A with g and a with G. Over many meioses the four kinds of gamete are made in equal numbers.

The theory was put to the test by Thomas Hunt Morgan and his students at Columbia University in New York, using the fruit fly Drosophila melanogaster. Several features made the fly ideal:

• A new generation every two weeks or so, so a year holds many generations.
• Hundreds of offspring from a single pair, enough for reliable ratios.
• Many inherited variants of eye colour, body colour and wings, visible with a hand lens or a low-power microscope.
• Cheap to keep: flies live in bottles on a simple artificial food.
• Males and females are easy to tell apart, and the cells have only four pairs of chromosomes.

Morgan's group showed that a particular gene lies on a particular chromosome, and his work earned the 1933 Nobel Prize in Physiology or Medicine. The fly is still one of biology's most useful model organisms.

4.3.3 Linkage and Recombination

Independent assortment has a built-in limit. A cell has far more genes than chromosomes (the fruit fly has thousands of genes but only four pairs of chromosomes), so many genes must share a chromosome, and genes sharing a chromosome should travel together. Morgan's group found exactly this. Take fly crosses involving two genes on the X chromosome, for example for eye colour and body colour. The grandparental combinations of characters reappeared far more often than 9 : 3 : 3 : 1 would allow, while new combinations were rare.

Morgan named the physical joining of genes on one chromosome linkage (सहलग्नता) and the production of new combinations of alleles recombination (पुनर्योजन). Linked genes can still recombine, through crossing over: during prophase I, two non-sister chromatids of a homologous pair break at matching points and rejoin, exchanging segments.

A clear example uses two genes on chromosome 2 of the fly: body colour (grey, $b^{+}$, dominant over black, $b$) and wing shape (normal, $v{g}^{+}$, dominant over vestigial, $vg$). Cross a true-breeding grey, normal-winged fly with a black, vestigial-winged one, and each ${\mathrm{F}}_1$ female carries $b^{+}$ and $v{g}^{+}$ on one chromosome 2 and $b$ and $vg$ on its homologue. Test-cross these females with black, vestigial males. (Females are used because crossing over does not happen in male fruit flies.) Independent assortment would give the four kinds of offspring in equal numbers. Instead, a typical batch looks like Table 4.5.

The two parental classes account for 664 of the 800 flies and the two recombinant classes for 136. The recombination frequency is the fraction of offspring that are recombinant: $136\mathrm{/}800=0.17$, or 17 %. Fig. 4.10 shows where the recombinants come from: only gametes in which a crossover fell somewhere between the two genes carry a new combination.

Why do some linked pairs recombine more than others? Alfred Sturtevant, a student in Morgan's laboratory, reasoned that crossovers happen at more or less random points along a chromosome. Two genes far apart give a crossover many chances to fall between them; two neighbours give it very few. So genes close together are tightly linked and rarely recombine, while genes far apart are loosely linked and recombine often. In 1913 Sturtevant turned this into a method: treating recombination frequency as a distance, he placed several X-chromosome genes in order along a line, the first genetic map. Today 1 % recombination defines one map unit, or one centimorgan (cM).

The frequency cannot rise above 50 %: genes so far apart that crossovers nearly always separate them assort as if they were unlinked. Maps built from recombination later guided the sequencing of whole genomes, the human genome among them (Chapter 5).

4.4 Polygenic Inheritance

Line your class up by height and you will not find two neat groups, like Mendel's tall and dwarf peas, but a smooth range with most people near the middle. Such continuous variation arises when many genes, each with a small effect, act on one character. The environment adds its own influence too: a well-fed child grows taller than the same child would on a poor diet. Characters of this kind are called polygenic, and polygenic inheritance (बहुजीनी वंशागति) shows how Mendel's discrete factors can still produce smooth variation, the very observation that once made biologists doubt him.

In the simplest model each contributing allele adds a fixed amount to the phenotype: the effects are additive. A classic case is the colour of wheat grains, studied by the Swedish geneticist Herman Nilsson-Ehle around 1909. Suppose two genes, A and B, control redness, each capital allele adding one dose of red pigment and each small allele adding none. AABB grains are dark red, aabb grains white, and AaBb grains, with two doses, medium red. Self the AaBb plants and the ${\mathrm{F}}_2$ falls into five shades according to the number of capital alleles, from 0 to 4, in the ratio 1 : 4 : 6 : 4 : 1 (Fig. 4.12).

With three such genes there are seven classes, from 0 to 6 doses, in the ratio 1 : 6 : 15 : 20 : 15 : 6 : 1, and the bars already trace a bell. Human skin colour has long been modelled in the same way, as several genes whose 'darker' alleles add up, with sunlight then adjusting the result. Add environmental effects to any polygenic character and the separate classes blur into the smooth curve we actually observe.

4.5 Pleiotropy

A baby with untreated phenylketonuria (PKU) develops several problems that look unrelated. The brain develops poorly, the urine contains an unusual acid, and the skin and hair are often paler than in the rest of the family. All of them trace back to one faulty gene, the gene for the enzyme phenylalanine hydroxylase, which normally turns the amino acid phenylalanine into tyrosine (Fig. 4.13). When one gene influences several different characters like this, the gene is called pleiotropic and the effect pleiotropy (बहुप्रभाविता).

How can one gene do so much? Usually its product works at a crossroads of the cell's chemistry. In PKU the blocked step has consequences in both directions. Phenylalanine piles up and harms the developing brain, causing intellectual disability; its by-product phenylpyruvic acid spills into the urine; and less tyrosine is left for making the pigment melanin.

The sickle-cell allele (Section 4.8.2) is pleiotropic too. One amino-acid change leads to anaemia, blocked small blood vessels, episodes of pain, damage to organs such as the spleen and, in carriers, some protection against malaria. In Marfan syndrome a fault in one connective-tissue protein affects the skeleton (long limbs and fingers), the lenses of the eyes and the main artery leaving the heart.

4.6 Sex Determination

Why do some offspring develop as males and others as females? The story begins in 1891 with Hermann Henking, who was watching sperm form in the firebug, an insect. One darkly staining nuclear body caught his eye: it ended up in only half of the sperm. Not knowing what it was, he simply called it the 'X body'. Others later showed it was a chromosome, and the name stuck: the X chromosome. Chromosomes involved in deciding sex are sex chromosomes; all the others are autosomes.

In grasshoppers and cockroaches the female's cells have two X chromosomes and the male's only one, with no partner: the XO type of sex determination. A male grasshopper therefore has one chromosome fewer than a female, and his sperm come in two kinds, with and without an X, while every egg has one. Which sperm fertilises the egg decides the sex: an X-bearing sperm gives an XX daughter, an X-less sperm an XO son.

Humans, other mammals and the fruit fly use the XY type. Females are XX; males have one X and a smaller partner, the Y chromosome, so the two sexes have the same number of chromosomes. Since it is the male whose sperm come in two kinds, both the XO and the XY systems are described as male heterogamety (hetero, different; gamety, gametes).

Birds reverse this. A hen has two different sex chromosomes, named Z and W to avoid confusion with X and Y, while a cock has two Z chromosomes; the chromosome number is again the same in both sexes. Here the female makes two kinds of egg, Z-bearing and W-bearing, in equal numbers, and the sex of a chick depends on which kind of egg was fertilised. This is female heterogamety; most butterflies and moths share it. Fig. 4.14 sets the three systems side by side.

4.6.1 Sex Determination in Humans

Every human egg is alike in one respect: it carries 22 autosomes and an X. Sperm are not alike. A man's cells have 22 pairs of autosomes plus an X and a Y, and meiosis puts the X into half of his sperm and the Y into the other half (Table 4.6). An egg fertilised by an X-bearing sperm becomes an XX zygote and develops as a girl. One fertilised by a Y-bearing sperm becomes XY and develops as a boy, because a gene on the Y, SRY, switches the developing gonads towards forming testes.

Two conclusions follow. The sex of a child is settled by the father's sperm, not by the mother. And since the two kinds of sperm are made in equal numbers and are equally likely to reach the egg, every pregnancy carries a 1/2 chance of a girl, whatever the sex of the earlier children.

4.6.2 Sex Determination in Honey Bee

A honey-bee colony has one queen, tens of thousands of female workers and, in season, some hundreds of male drones. Whether an egg becomes female or male depends on whether it was fertilised at all. The queen stores sperm from her mating flights and releases it, or not, as each egg is laid. A fertilised egg receives two chromosome sets (2n = 32) and becomes a female: a worker or, if the larva is fed royal jelly throughout, a queen. An unfertilised egg develops anyway, by parthenogenesis, into a haploid drone (n = 16) (Fig. 4.15). Sex here is set by the number of chromosome sets, so the system is called haplodiploid.

Family trees in such a species look odd. Draw a drone's ancestry: he has a mother but no father, while his mother had both, so he does have a grandfather. He makes sperm by mitosis, since he has only one set of chromosomes to start with. His sperm can only ever fertilise eggs that become daughters, so he can never have sons; through those daughters, though, he can have grandsons.

4.7 Mutation

Recombination shuffles existing alleles into new combinations. Mutation (उत्परिवर्तन) is the other great source of variation: a change in the DNA sequence itself, which can change the genotype and, through it, the phenotype.

Mutations range from huge to tiny. At the large end, whole segments of a chromosome are lost (deletion) or gained (insertion or duplication). Since a chromosome is essentially one continuous, tightly packed DNA molecule (Chapter 5), such a change removes or repeats every gene in the segment. These chromosomal aberrations are a hallmark of many cancer cells; in chronic myeloid leukaemia, for example, parts of chromosomes 9 and 22 have changed places.

At the smallest scale a single base pair may change: a point mutation. The best-known example is sickle-cell anaemia, in which one base substitution alters one amino acid of β-globin (Fig. 4.16). Inserting or deleting a base inside a gene usually does far more harm. The cell reads a gene in consecutive groups of three bases (codons), so every codon after the change is misread, unless exactly three bases are gained or lost. These are frame-shift mutations.

Mutations arise by chance, for example as copying errors when DNA is replicated, and agents in the environment raise their rate. These mutagens include physical agents such as UV radiation (one reason repeated sunburn raises the risk of skin cancer), X-rays and gamma rays, and chemical agents, among them several substances in tobacco smoke. The molecular mechanisms of mutation lie beyond this chapter.

4.8 Genetic Disorders

Many of the mutations of Section 4.7 that matter for health are inherited, carried down families just as Mendel's alleles are. This section looks at the disorders they cause and at how geneticists trace them.

4.8.1 Pedigree Analysis

A geneticist studying peas can cross any two plants and count hundreds of offspring the next season. A geneticist studying people can do neither: families are small, generations are long, and nobody arranges marriages for an experiment. Human genetics relies instead on records of families that already exist. Drawn as a chart across several generations, with everyone who shows a particular trait marked, such a record is a pedigree. Working out from it how the trait is inherited is pedigree analysis (वंशावली विश्लेषण). People had long known that some conditions run in families, and systematic pedigree studies began soon after Mendel's work was rediscovered. Fig. 4.17 shows the standard symbols.

Read a pedigree from the top. Each row is a generation, numbered with Roman numerals. Within a row, a line joining two symbols is a mating, and their children hang from a horizontal line below it, oldest on the left. Carriers, people with one copy of a recessive allele who are not affected themselves, are often marked with a dot once they are known.

4.8.2 Mendelian Disorders

Inherited disorders come in two broad kinds. A Mendelian disorder results from a change in one gene, so it follows Mendel's rules from generation to generation and can be tracked through pedigrees. Examples include thalassaemia, sickle-cell anaemia, phenylketonuria, cystic fibrosis, haemophilia and colour blindness. A chromosomal disorder results from missing, extra or rearranged chromosomes (Section 4.8.3).

Two questions classify a Mendelian disorder: is the faulty allele dominant or recessive, and does it sit on an autosome or on the X chromosome? A well-drawn pedigree usually answers both. Fig. 4.18 shows one family for each of the three common patterns, with the clue that settles it:

• Autosomal recessive: two unaffected parents can have an affected child, because both are carriers; daughters and sons are affected alike. Examples: sickle-cell anaemia, thalassaemia, phenylketonuria, cystic fibrosis.
• Autosomal dominant: every affected person has at least one affected parent, so the trait appears in every generation; two affected parents can have an unaffected child; it can pass from father to son. Examples: myotonic dystrophy, Huntington disease.
• X-linked recessive: many more males are affected than females; affected sons usually have unaffected carrier mothers; it never passes from father to son, because a father gives his son a Y, not an X. Examples: haemophilia, red–green colour blindness.

Colour blindness. Why is red–green colour blindness so much commoner in men, affecting around 8 % of men in many populations but well under 1 % of women? The genes for the red-sensing and green-sensing pigments of the eye's cone cells lie on the X chromosome, and the faulty alleles that make red and green hard to tell apart are recessive. A man, with a single X, is colour blind whenever that X carries a faulty allele. A woman needs faulty alleles on both her X chromosomes, which is far less likely. With one, she is an unaffected carrier, and each of her sons has a 1/2 chance of being colour blind (Example).

Haemophilia. The most famous carrier of haemophilia was Queen Victoria of Britain: one of her sons was affected, and two of her daughters were carriers whose own daughters took the allele into the royal families of Spain and Russia. The disorder is X-linked recessive. Normal clotting depends on a cascade of proteins, each switching on the next. In haemophilia one of these proteins is missing or faulty, so bleeding from a small cut, or into a joint, is hard to stop. Affected girls are very rare, since a girl would need an affected father as well as a carrier mother, and until modern treatment few affected men lived long enough to become fathers.

Sickle-cell anaemia. Under a microscope, blood from a person with this disease shows many red cells bent into stiff crescents instead of soft, round discs. The cause lies in haemoglobin. When oxygen is scarce, the person's haemoglobin molecules link up into long rods that stretch the cell out of shape. Sickled cells jam small blood vessels, causing pain and organ damage, and are destroyed early, causing anaemia.

The faulty haemoglobin differs from the normal kind in one amino acid out of the 146 in its β chain: valine (Val) instead of glutamic acid (Glu) at position 6. That in turn comes from a single base: the sixth codon of the β-globin gene reads GTG instead of GAG in the DNA, or GUG instead of GAG in the mRNA (Fig. 4.16).

The disorder is autosomal recessive, with two alleles, $H{b}^A$ and $H{b}^S$. Only $H{b}^{S}H{b}^S$ people have the disease. Carriers ($H{b}^{A}H{b}^S$) are usually healthy but pass $H{b}^S$ to half their children on average, so a couple of carriers has a 1/4 chance with each child of an affected baby. The disease is common in several tribal communities of central and western India, where a national mission launched in 2023 aims to screen for it and to eliminate it as a public-health problem by 2047.

Phenylketonuria. We met PKU as an example of pleiotropy (Section 4.5). It is an inborn error of metabolism inherited as an autosomal recessive. Only children with two faulty copies of the enzyme gene are affected, so carrier parents have a 1/4 chance of an affected child each time. The kidneys reabsorb phenylalanine's by-products poorly, which is why they appear in the urine. A blood test soon after birth, followed by a diet low in phenylalanine, prevents most of the brain damage.

Thalassaemia. Adult haemoglobin is built from two kinds of globin chain, α and β, in equal numbers. In thalassaemia a mutation or deletion slows the production of one kind, so the cell cannot assemble enough normal haemoglobin and the person is anaemic. Like sickle-cell anaemia it is autosomal recessive: affected children are usually born to two healthy carriers. Its two main forms are named after the chain in short supply:

• α-thalassaemia: α-globin production falls. Two neighbouring genes on chromosome 16, HBA1 and HBA2, both code for α-globin, and with one chromosome 16 from each parent a person has four such genes. The more of the four that are deleted or damaged, the less α-globin the cells can make.
• β-thalassaemia: β-globin production falls. Here only one gene is involved, HBB on chromosome 11, and the disorder follows from mutations in one or both of a person's two copies.

4.8.3 Chromosomal Disorders

Chromosomes, too, can be miscounted. During meiosis the two members of a pair, or two sister chromatids, occasionally fail to part, an error called nondisjunction. One gamete then carries an extra copy of that chromosome and its partner gamete carries none (Fig. 4.19). Fertilised by a normal gamete, they give zygotes with three copies (trisomy, 2n + 1) or one copy (monosomy, 2n − 1) of the chromosome. Gaining or losing individual chromosomes in this way is aneuploidy (असुगुणिता). Human cells normally hold 46 chromosomes, 22 pairs of autosomes and one pair of sex chromosomes; most aneuploid embryos do not survive, and those that do have a chromosomal disorder.

A cell can also gain a complete extra set of chromosomes, for instance when cytokinesis fails after telophase so that the doubled chromosomes stay together in one cell. This is polyploidy. Rare and usually lethal in animals, it is common in plants: bread wheat is hexaploid (six sets) and most edible bananas are triploid (three sets).

Chromosomal disorders are diagnosed from a karyotype, a picture of a cell's chromosomes arranged in pairs by size and shape. Three common examples are compared in Table 4.8:

Down's syndrome (trisomy 21, 47 chromosomes) is the best known of the three, and its risk rises with the mother's age. John Langdon Down described it in 1866, long before its cause was known. People with the syndrome typically have delayed physical, psychomotor and mental development and short stature. Other common features are a broad palm often crossed by a single crease, a small round head with a furrowed tongue and partly open mouth, and quite often a heart defect present from birth.

The other two involve the sex chromosomes, and together they show that the Y, not the number of X chromosomes, decides maleness. A person with Klinefelter's syndrome has two X chromosomes and a Y (47, XXY). The Y makes him male, but the extra X can bring some female features such as breast development (gynaecomastia), and he is sterile. A person with Turner's syndrome has a single X and no Y (45, X0). She develops as a female, usually short, but her ovaries stay rudimentary, so she is sterile and does not develop the other secondary sexual characters.