Principles of Inheritance and Variation

Genetics is the branch of biology that studies inheritance (the passing of characters from parent to progeny) and variation (the degree to which progeny differ from their parents). Gregor Mendel did hybridisation experiments on garden pea (Pisum sativum) for seven years, 1856–1863, and proposed the laws of inheritance in living organisms. He was the first to apply statistical analysis and mathematical logic to biology, and he worked with large sample sizes, which made his data credible.

He chose true-breeding pea lines: a line that has undergone continuous self-pollination and shows stable trait inheritance and expression for several generations. He selected 14 true-breeding varieties as 7 pairs of contrasting traits, each pair differing in a single character:

• Stem height: tall / dwarf
• Flower colour: violet / white
• Flower position: axial / terminal
• Pod shape: inflated / constricted
• Pod colour: green / yellow
• Seed shape: round / wrinkled
• Seed colour: yellow / green

The examiner also wants the reasons for choosing pea: many easily distinguishable contrasting characters; bisexual flowers that normally self-pollinate, so true-breeding lines are easy to maintain and cross-pollination can be done by hand (emasculation and bagging); a short life cycle with a large number of seeds per generation; and the plant is easy to grow.

His method was simple. He crossed two true-breeding parents differing in one character (a monohybrid cross) or two characters (a dihybrid cross), collected the hybrid seeds (the F₁ or first filial generation), then self-pollinated the F₁ to get the F₂, and counted every plant in each class. The ratios he found are the whole basis of the chapter.

Mendel crossed a true-breeding tall plant with a true-breeding dwarf plant. Every F₁ plant was tall: neither intermediate nor a mixture, and it made no difference which parent supplied the pollen (reciprocal crosses gave the same result). When the F₁ was selfed, the F₂ had tall and dwarf plants in the ratio 3 : 1, and the dwarf plants were exactly like the original dwarf parent. He got the same 3 : 1 pattern for all seven characters.

Mendel's explanation, still the way the examiner wants it written:

• Each character is controlled by a pair of factors (now called genes) that are passed from parent to offspring through gametes.
• Genes that code for a pair of contrasting traits are called alleles: slightly different forms of the same gene, written as a capital letter (T) for the dominant and a small letter (t) for the recessive allele.
• The two alleles are TT in a true-breeding tall plant, tt in a true-breeding dwarf plant. Gametes carry only one allele of the pair, so TT × tt gives F₁ plants that are all Tt, tall because T is dominant over t.
• TT and tt are homozygous (both alleles identical); Tt is heterozygous (two different alleles); a heterozygote is also called a hybrid.
• Genotype is the genetic constitution (TT, Tt, tt); phenotype is the observable trait (tall or dwarf). TT and Tt look identical, so a tall plant can have either genotype.

Mendel's F₁ Tt plants produce two kinds of gametes, T and t, in equal number. Fusion is random. The Punnett square (devised by R. C. Punnett) tabulates every gamete combination: TT, Tt, Tt, tt. So the F₂ has a genotypic ratio 1 TT : 2 Tt : 1 tt and a phenotypic ratio 3 tall : 1 dwarf. Genes in a diploid organism come in pairs, and each parent contributes one allele of every gene to each gamete, which is why the ratio is what it is.

From the monohybrid cross Mendel derived his first two laws. The Law of Dominance states:

1. Characters are controlled by discrete units called factors.
2. Factors occur in pairs.
3. In a dissimilar pair of factors, one member of the pair dominates (dominant) the other (recessive).

The law explains why only one parental character is seen in the F₁, and why both appear in the F₂ in the proportion 3 : 1.

NCERT gives a molecular picture of what 'dominant' means, and a 2- or 3-mark question sometimes asks for it. A gene contains the information to make a particular product, usually an enzyme. The normal (unmodified) allele makes the normal enzyme. A modified allele can (a) make the normal or less efficient enzyme, (b) make a non-functional enzyme, or (c) make no enzyme at all. In case (a) the modified allele is equivalent to the unmodified one and both produce the same phenotype. In cases (b) and (c) the phenotype depends only on the unmodified allele, which therefore appears dominant; the modified allele is recessive because it does not produce a functional product. The example NCERT uses is the enzyme for starch synthesis in pea seeds: BB makes it efficiently, bb poorly, and Bb makes enough for round seeds, so B is dominant for seed shape.

Two points the examiner looks for. First, dominance is not a property of a gene by itself; it depends on which phenotype you observe (see incomplete dominance for starch grain size). Second, a recessive allele is not lost in the F₁; it is merely masked and reappears unchanged in the F₂. That reappearance is the proof that the factors stay discrete and do not blend.

The Law of Segregation says that the two alleles of a character do not blend in the hybrid; when gametes are formed the two factors segregate (separate) so that each gamete receives only one of them. A homozygous parent produces only one kind of gamete; a heterozygous parent produces two kinds in equal proportion. This law has no exception, which is why NCERT calls it a universally accepted law.

Because TT and Tt are both tall, you cannot tell the genotype of a tall plant by looking at it. Mendel's solution was the test cross: cross the organism of dominant phenotype with its homozygous recessive parent (or any homozygous recessive). Two outcomes are possible:

• If the tall plant is TT: TT × tt → all progeny Tt, all tall. No recessive phenotype appears.
• If the tall plant is Tt: Tt × tt → 1 Tt : 1 tt, that is 1 tall : 1 dwarf. The appearance of dwarf progeny proves the parent was heterozygous.

So a test cross reveals the genotype of an individual showing the dominant phenotype, and it also demonstrates segregation, because the recessive allele reappears in half the progeny. For two genes the dihybrid test cross of a double heterozygote RrYy with rryy gives 1 : 1 : 1 : 1 (round yellow : round green : wrinkled yellow : wrinkled green).

Contrast this with a back cross, which is a cross of the F₁ with either of its parents; the test cross is the special case with the recessive parent. Mendel also selfed the F₂ tall plants and found one-third bred true (TT) and two-thirds produced 3 : 1 again (Tt), which independently confirms the 1 : 2 : 1 genotypic ratio.

A worked pattern from the board: 'A tall pea plant on selfing gave 25% dwarf offspring. What is its genotype?' Answer: Tt, because only a heterozygote gives 3 tall : 1 dwarf on selfing; show the Punnett square.

After Mendel's work was rediscovered, other characters were found where the F₁ did not resemble either parent but was in between. This is incomplete dominance. The standard example is flower colour in the dog flower (snapdragon, Antirrhinum sp.).

A true-breeding red-flowered plant (RR) crossed with a true-breeding white-flowered plant (rr) gives an F₁ that is all pink (Rr). Selfing the F₁ gives an F₂ of 1 red (RR) : 2 pink (Rr) : 1 white (rr). The genotypic ratio is Mendel's usual 1 : 2 : 1, but the phenotypic ratio is also 1 : 2 : 1 instead of 3 : 1, because the heterozygote has its own phenotype. Write the cross out fully: parents, gametes, F₁, F₁ gametes, the four-box Punnett square, and both ratios. The examiner rewards that structure.

Here R is not completely dominant over r, so the intermediate colour appears: one dose of R gives less pigment than two. NCERT's second example is the starch grain size in pea mentioned under dominance. BB seeds have large starch grains and are round; bb seeds have small grains and are wrinkled; Bb seeds are round (so B looks dominant for seed shape) but their starch grains are of intermediate size. Whether a pair of alleles shows complete or incomplete dominance therefore depends on which phenotype you score.

Two things to keep straight. Incomplete dominance is not blending inheritance: the alleles stay separate, and pure red and pure white plants come back in the F₂. And the terms 'dominant' and 'recessive' still make sense at the molecular level; the recessive allele simply produces no functional product, and one working copy is not enough for the full phenotype.

In co-dominance the F₁ resembles both parents: both alleles express themselves fully and independently in the heterozygote, and no intermediate phenotype forms. The NCERT example is the ABO blood grouping in humans.

ABO blood groups are controlled by a single gene I, which has three alleles: I^A, I^B and i. The gene codes for an enzyme that adds a sugar to the surface of the red blood cell plasma membrane. I^A and I^B each produce a slightly different sugar, so they are the A antigen and B antigen respectively; i does not produce any sugar. A person carries any two of the three alleles. I^A and I^B are both completely dominant over i, but when I^A and I^B are together each expresses its own sugar, so the person has both antigens: blood group AB. That is co-dominance.

Three alleles give six genotypes and four phenotypes:

• I^AI^A and I^Ai → group A
• I^BI^B and I^Bi → group B
• I^AI^B → group AB
• ii → group O

The ABO system also illustrates multiple allelism: a gene existing in more than two allelic forms in a population. Any one diploid individual still carries only two of them; the third can be seen only when the population is considered. Many board questions cross blood groups. The classic is NCERT exercise 12: a child of group O born to an A father and a B mother forces the parents to be I^Ai × I^Bi, and the other children can be I^AI^B (AB), I^Ai (A), I^Bi (B) or ii (O) in a 1 : 1 : 1 : 1 ratio.

Distinguish clearly for the examiner. In dominance the F₁ looks like one parent (pea: TT × tt → all tall); in incomplete dominance the F₁ is intermediate (snapdragon: pink); in co-dominance the F₁ shows both parental traits (I^AI^B has both antigens).

Mendel then crossed pea plants differing in two characters, for example seed colour and seed shape. A true-breeding plant with round yellow seeds (RRYY) was crossed with one with wrinkled green seeds (rryy). Every F₁ seed was round and yellow (RrYy), so yellow is dominant over green and round over wrinkled, just as the monohybrid crosses had shown.

Selfing the F₁ gave an F₂ with four phenotypes in the ratio 9 round yellow : 3 round green : 3 wrinkled yellow : 1 wrinkled green (Mendel's counts were 315 : 108 : 101 : 32). If you look at one character at a time, round : wrinkled is (9 + 3) : (3 + 1) = 3 : 1, and yellow : green is also 3 : 1. Each gene is behaving exactly as in a monohybrid cross, independently of the other.

The F₁ RrYy plant makes four kinds of gametes, RY, Ry, rY, ry, each 1/4, because the alleles of one gene assort into gametes independently of the alleles of the other. Placing these on both sides of a 4 × 4 Punnett square gives 16 combinations that sort into 9 : 3 : 3 : 1. Genotypically there are nine classes (1 RRYY : 2 RRYy : 2 RrYY : 4 RrYy : 1 RRyy : 2 Rryy : 1 rrYY : 2 rrYy : 1 rryy).

From this Mendel proposed the Law of Independent Assortment: when two pairs of traits are combined in a hybrid, segregation of one pair of characters is independent of the other pair of characters. The 9 : 3 : 3 : 1 ratio is a product of two 3 : 1 ratios, (3 : 1) × (3 : 1), which is why it holds only when the genes are on different chromosomes or far apart on the same one.

The dihybrid test cross RrYy × rryy gives 1 : 1 : 1 : 1 and is used to prove independent assortment directly, since the recessive parent contributes only ry and the progeny phenotypes read off the F₁ gametes. NCERT exercise 7 uses the same logic for TtYy × Ttyy: treat each gene separately (tall : dwarf = 3 : 1, yellow : green = 1 : 1) and multiply the fractions.

Mendel published his work in 1865 but it went unrecognised until 1900. NCERT gives four reasons, and a 3-mark question asks for them: communication was not easy in those days, so the work spread slowly; his idea of factors as stable, discrete units that did not blend was not accepted by contemporaries who believed in blending; his mathematical approach to a biological problem was new and unacceptable to biologists; and he could not give any physical proof of what the factors were or what they were made of.

In 1900 three scientists, de Vries, Correns and von Tschermak, independently rediscovered Mendel's results. By then microscopy had improved, cell division was understood, and chromosomes had been seen: structures in the nucleus that double and divide just before cell division. In 1902 Walter Sutton and Theodore Boveri noticed that the behaviour of chromosomes during meiosis was parallel to the behaviour of Mendel's factors, and used chromosome movement to explain Mendel's laws. This is the chromosomal theory of inheritance: genes are located on chromosomes, and it is the chromosomes that segregate and assort independently.

The parallels the examiner expects, as a table or list:

• Chromosomes occur in pairs; so do genes (factors).
• Homologous chromosomes separate at meiosis so each gamete gets one; alleles of a gene pair segregate the same way.
• One member of each pair comes from each parent; one allele of each gene comes from each parent.
• Different chromosome pairs segregate independently at anaphase I; different gene pairs assort independently.

Genes are therefore located at fixed positions (loci) on chromosomes, both alleles of a gene pair occupy the same locus on the two homologous chromosomes, and the segregation of a chromosome pair at anaphase I of meiosis is the physical basis of the law of segregation. The independent orientation of different bivalents at metaphase I is the physical basis of independent assortment.

Experimental proof came from Thomas Hunt Morgan and his colleagues, who worked on the tiny fruit fly Drosophila melanogaster. Morgan chose it because it grows on a simple synthetic medium in the laboratory, completes its life cycle in about two weeks, a single mating produces a large number of progeny, it shows clear sexual dimorphism (males and females easily told apart), and it has many hereditary variations that can be seen with a low-power microscope.

Morgan carried out several dihybrid crosses in Drosophila with pairs of genes that were sex-linked (on the X chromosome) to test whether such genes obeyed independent assortment. He found that when two genes were on the same chromosome, the proportion of parental gene combinations in the F₂ was much higher than the non-parental type, which is not what 9 : 3 : 3 : 1 predicts.

He explained this by the physical association of the genes. Genes lying on the same chromosome tend to be inherited together; Morgan called this linkage. The generation of non-parental combinations is recombination, and it happens by crossing over between homologous chromosomes at meiosis. The closer two genes lie, the less often a cross-over falls between them, so they are tightly linked and show little recombination; genes farther apart are loosely linked and recombine more often.

The two crosses in NCERT and the numbers the examiner wants:

• Cross A: yellow body (y) and white eyes (w). F₂ had 98.7% parental types and only 1.3% recombinants: the genes are very tightly linked.
• Cross B: white eyes (w) and miniature wings (m). F₂ had 62.8% parental types and 37.2% recombinants: the genes are on the same chromosome but farther apart, so they recombine more.

Morgan's student Alfred Sturtevant used the frequency of recombination between gene pairs on the same chromosome as a measure of the distance between them, and 'mapped' their positions on the chromosome. These genetic maps were used later as the starting point for sequencing whole genomes in the Human Genome Project.

Linkage is the main exception to the law of independent assortment. Independent assortment applies to genes on different chromosomes; genes on the same chromosome assort together, and only crossing over breaks the linkage partially. The strength of linkage is inversely proportional to the distance between the genes; the recombination frequency is directly proportional to it. NCERT exercise 8 asks what happens in a dihybrid cross of two heterozygotes when the loci are linked: the F₂ does not give 9 : 3 : 3 : 1; parental phenotypes predominate and recombinants are few (with complete linkage the two genes behave as one and give 3 : 1).

Mendel studied characters with two distinct alternative forms, tall or dwarf, round or wrinkled. Many traits are not like that; they show a gradation of phenotypes across a whole range, such as human height or skin colour. Such traits are controlled by three or more genes and are called polygenic traits. The phenotype reflects the additive contribution of each allele, and it is also influenced by the environment (nutrition affects height, sunlight affects skin colour).

NCERT's example is human skin colour, assumed to be controlled by three genes A, B and C. The dominant forms A, B and C are responsible for dark skin and the recessive a, b and c for light skin. A genotype with all the dominant alleles (AABBCC) is the darkest, and one with all the recessive alleles (aabbcc) is the lightest. The genotype with three dominant and three recessive alleles (AaBbCc) has an intermediate colour. In this model the phenotype depends only on the number of dominant alleles present, not on which genes they belong to: AABbcc, AaBBcc and aaBbCC all have three dominant alleles and the same intermediate skin colour.

If two intermediate parents AaBbCc × AaBbCc mate, each makes 8 kinds of gametes and the 64 combinations give seven skin-colour classes (0 to 6 dominant alleles) in the proportion 1 : 6 : 15 : 20 : 15 : 6 : 1, which plots as a bell-shaped curve. You will not be asked to draw the square, but you may be asked to say why the distribution is continuous: because each dominant allele adds a small equal amount of pigment.

Do not confuse polygenic inheritance with pleiotropy; they are opposites in a sense. In polygenic inheritance many genes control one character; in pleiotropy one gene controls many characters. A frequent 2-mark question asks exactly this difference with one example of each.

Normally we think of one gene controlling one trait. Sometimes a single gene shows multiple phenotypic expressions: it controls several apparently unrelated characters. This is pleiotropy, and the gene is a pleiotropic gene. The underlying mechanism is usually the effect of the gene on a metabolic pathway that contributes to several phenotypes.

NCERT's first example is phenylketonuria, an inherited human disease caused by a mutation in the gene that codes for the enzyme phenylalanine hydroxylase. The one gene defect produces several phenotypic effects: mental retardation, and a reduction in hair and skin pigmentation (because tyrosine, which is not made from phenylalanine, is also the precursor of the pigment melanin).

The second example is the starch synthesis gene in pea. The same gene B decides seed shape (round or wrinkled) and starch grain size (large or small), so it is pleiotropic; and it shows complete dominance for one phenotype and incomplete dominance for the other. Sickle cell anaemia is another example often accepted: the single HbS allele causes sickle-shaped cells, anaemia, spleen damage and reduced malaria susceptibility.

The examiner tends to ask for comparisons, so keep these three apart:

• Multiple allelism: one gene has more than two alleles in the population (ABO blood group gene I with I^A, I^B, i).
• Polygenic inheritance: many genes together control one trait, with additive effects (skin colour, height).
• Pleiotropy: one gene affects many traits (phenylketonuria, pea starch gene).

A frequent trap: 'a gene with multiple alleles' is not the same as 'a gene with multiple effects'. Multiple alleles is about how many versions a gene has; pleiotropy is about how many phenotypes one version influences.

The mechanism of sex determination has always puzzled geneticists. The first clue came from cytological work in insects. Henking (1891) traced a specific nuclear structure through spermatogenesis in some insects and found that 50 per cent of the sperm received it and 50 per cent did not. He called it the X body; it was later shown to be a chromosome, the X chromosome.

Four patterns are asked in boards. Learn them as a table of which sex produces two kinds of gametes (heterogametic) and which produces only one kind (homogametic).

• XX–XO type (grasshopper and many insects): females have two X chromosomes (XX); males have only one X (XO). Males produce two kinds of sperm, half with X and half without any X; all eggs carry X. Eggs fertilised by X-sperm become females, those by no-X sperm become males. Male heterogamety.
• XX–XY type (humans, Drosophila, many other insects and mammals): both sexes have the same number of chromosomes; females have XX and males have one X and one smaller Y chromosome. Males produce two kinds of sperm (X or Y) in equal numbers; females produce only X eggs. Male heterogamety.
• ZW–ZZ type (birds): the female has two dissimilar sex chromosomes (ZW) and the male two similar (ZZ). The female produces two kinds of eggs (Z or W) and the male one kind of sperm (Z). Female heterogamety.
• Haplodiploidy (honey bee): sex depends on the number of chromosome sets, not on sex chromosomes; see the next section.

Sex determination in humans: humans have 23 pairs of chromosomes, 22 pairs of autosomes and one pair of sex chromosomes. A female is XX, a male XY. During spermatogenesis the male produces two types of gametes, 50 per cent carrying X and 50 per cent carrying Y, along with 22 autosomes each; the female produces only X-carrying ova. If an ovum is fertilised by an X-sperm the zygote is XX (female); by a Y-sperm, XY (male). So the sex of the child is decided by the sperm, that is by the father, and the probability of a boy or a girl at each conception is 50 : 50. This is the scientific answer to 'do women determine the sex of the child?': no, the genetic makeup of the sperm does, and it is unfortunate that women are blamed for the sex of the child.

The honey bee has a sex-determination system that does not use sex chromosomes at all; it depends on the number of sets of chromosomes an individual receives. This is called haplodiploidy (a haplodiploid sex-determination system).

An egg that is fertilised by a sperm develops into a female, either a queen or a worker. An egg that is not fertilised develops into a male (drone) by parthenogenesis. Females are therefore diploid with 32 chromosomes, and males are haploid with 16 chromosomes. Whether a fertilised egg becomes a queen or a worker is decided by the diet fed to the larva, not by genetics, but that is beyond the syllabus; what the paper asks is the chromosome logic.

Three consequences follow, and they turn up as assertion-reason and MCQ items:

• The male produces sperm by mitosis, not meiosis, because a haploid cell cannot undergo meiosis. All the sperm of one drone are genetically identical to each other and to him.
• A drone has no father (he came from an unfertilised egg) and cannot have sons (his sperm only ever fertilise eggs, which become daughters).
• But a drone does have a grandfather (his mother, the queen, had a father) and can have grandsons (his daughters can lay unfertilised eggs).

Compare with the other systems for a 5-mark answer: in humans, grasshopper and birds the sex-determining factor is a sex chromosome and one sex is heterogametic; in honey bee there is no heterogametic sex and the determining factor is ploidy. A queen controls the sex of her offspring by choosing whether to release stored sperm on to an egg as she lays it.

Mutation is a phenomenon that results in the alteration of the DNA sequence, and consequently a change in the genotype and the phenotype of an organism. Along with recombination, mutation is the source of the variation on which selection acts.

NCERT distinguishes the kinds by scale:

• Chromosomal aberrations: loss (deletion) or gain (insertion/duplication) of a segment of DNA. Such aberrations are commonly observed in cancer cells.
• Point mutation: a mutation arising from a change in a single base pair of DNA. The classic example is sickle cell anaemia, in which one base substitution in the gene for the β-globin chain of haemoglobin changes the sixth codon from GAG to GUG, so glutamic acid is replaced by valine.
• Frameshift mutation: deletion or insertion of base pairs, which shifts the reading frame of the gene from the point of the change onwards, so every codon after it is read wrongly and the protein is usually non-functional. (Insertions or deletions of three bases, or multiples of three, do not shift the frame; Chapter 5 links this to the triplet code.)

Agents that cause mutation are mutagens: physical agents such as UV radiation and ionising radiation, and chemical agents. Many chemical and physical factors induce mutations.

For a 2-mark comparison: a point mutation changes one base and at most one amino acid (sickle cell anaemia); a frameshift mutation changes the reading of every codon downstream and alters many amino acids. Both are gene mutations, as opposed to chromosomal mutations that change the number of chromosomes (aneuploidy, polyploidy), which are dealt with under chromosomal disorders.

Mendel's laws of inheritance apply to humans as well, but controlled crosses are impossible. Since the idea of the 'factor' was accepted, human geneticists have studied the inheritance of a trait in a family tree over several generations; this is pedigree analysis. Whether a trait is dominant or recessive, autosomal or sex-linked, can be read from the pattern in the chart, which is why pedigrees are used in genetic counselling and in tracing hereditary diseases such as haemophilia, colour blindness and sickle cell anaemia.

The symbols you must know (NCERT Figure 4.13): a square for a male, a circle for a female, a diamond for sex unspecified, a horizontal line between a square and a circle for mating, a double line for a consanguineous mating (between relatives), a vertical line dropping to a horizontal sibship line for the offspring, shaded symbols for affected individuals, and a number inside a symbol for that many unaffected offspring of that sex. Generations are numbered I, II, III down the left.

How to read a chart, with the marking points:

• If two unaffected parents have an affected child, the trait is recessive (both parents are carriers). If every affected child has an affected parent and the trait appears in every generation, it is most likely dominant.
• If affected individuals are almost all males, and the trait skips a generation by passing through an unaffected (carrier) mother to her son, it is X-linked recessive (haemophilia, colour blindness).
• If males and females are affected about equally, the trait is autosomal (sickle cell anaemia, thalassaemia, phenylketonuria are autosomal recessive; myotonic dystrophy is NCERT's example of an autosomal dominant trait).

Genetic disorders are grouped into two: Mendelian disorders, caused by alteration or mutation in a single gene and transmitted in Mendelian patterns (they may be dominant or recessive, autosomal or sex-linked), and chromosomal disorders, caused by the absence or excess or abnormal arrangement of one or more chromosomes. The next two sections take them in turn.

Haemophilia is a sex-linked (X-linked) recessive disease that is transmitted from an unaffected carrier female to some of her male progeny. A single protein in the cascade of proteins involved in blood clotting is affected, so in an affected person even a simple cut leads to non-stop bleeding. The heterozygous female (X^HX^h) is a carrier and may transmit the disease to her sons: half her sons are haemophilic. A haemophilic female is extremely rare, because her mother would have to be at least a carrier and her father haemophilic, which is unviable in later life. A haemophilic father gives his X chromosome to all his daughters (who become carriers) and his Y to his sons, so he can never pass haemophilia to his son. Queen Victoria's pedigree shows several haemophilic descendants because she was a carrier.

Colour blindness (red-green) is also X-linked recessive, due to a defect in either the red or the green cone of the eye. It affects about 8 per cent of males and only about 0.4 per cent of females, because the gene is on the X chromosome and a male has only one X. A son of a carrier mother has a 50 per cent chance of being colour blind; a daughter is colour blind only if her mother is at least a carrier and her father is colour blind.

Sickle cell anaemia is an autosomal recessive trait controlled by a single pair of alleles, Hb^A and Hb^S. Only homozygous Hb^SHb^S individuals show the disease; heterozygous Hb^AHb^S individuals appear unaffected but are carriers, and two carriers have a 25 per cent chance of a diseased child. The defect is a substitution of glutamic acid by valine at the sixth position of the β-globin chain of haemoglobin, caused by the single base substitution GAG → GUG in the sixth codon. The mutant haemoglobin polymerises under low oxygen tension, changing the biconcave RBC into an elongated sickle shape.

Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism. The affected person lacks the enzyme phenylalanine hydroxylase, which converts phenylalanine to tyrosine. Phenylalanine accumulates and is converted into phenylpyruvic acid and other derivatives, which accumulate in the brain and cause mental retardation; they are also excreted through the kidney in the urine.

Thalassaemia is an autosomal recessive blood disease transmitted from unaffected carrier parents to some of their offspring. It results from a mutation or deletion that reduces the rate of synthesis of one of the globin chains (α or β) of haemoglobin, giving abnormal haemoglobin and anaemia. α-thalassaemia is caused by mutation or deletion of one or more of the four genes HBA1 and HBA2 on chromosome 16 (the more genes affected, the less α-globin made); β-thalassaemia by mutation of one or both of the HBB genes on chromosome 11. Thalassaemia is a quantitative problem (too few globin molecules), whereas sickle cell anaemia is a qualitative problem (an incorrectly functioning globin). That contrast is a regular 2-mark question.

Chromosomal disorders are caused by the absence or excess or abnormal arrangement of one or more chromosomes. Two kinds of change in number are defined in NCERT:

• Aneuploidy: failure of segregation of chromatids during cell division (non-disjunction) causes the gain or loss of a chromosome or chromosomes. A gamete with an extra chromosome produces a trisomic zygote (2n + 1); one missing a chromosome produces a monosomic zygote (2n − 1).
• Polyploidy: failure of cytokinesis after telophase of cell division results in an increase in a whole set of chromosomes (3n, 4n). It is rare in animals but often observed in plants.

Humans have 46 chromosomes (23 pairs). The three syndromes in the syllabus are all aneuploidies, and a table of them is a standard 3-mark question.

Down's syndrome: the presence of an additional copy of chromosome 21 (trisomy 21), giving 47 chromosomes. First described by Langdon Down (1866). The affected individual is short-statured with a small round head, furrowed tongue and partially open mouth; the palm is broad with a characteristic palm crease; physical, psychomotor and mental development is retarded. It is an autosomal aneuploidy, so it occurs in both sexes.

Klinefelter's syndrome: caused by the presence of an additional copy of the X chromosome, giving the karyotype XXY (47 chromosomes). The individual has overall masculine development but also expresses feminine development, such as development of breasts (gynaecomastia); such individuals are sterile.

Turner's syndrome: caused by the absence of one X chromosome, giving XO (45 chromosomes). Such females are sterile, with rudimentary ovaries, and lack other secondary sexual characters.

Points that separate marks: Down's is trisomy of an autosome, the other two are sex-chromosome aneuploidies; Klinefelter's is a male with an extra X, Turner's a female with a missing X; the mechanism behind all three is non-disjunction during gamete formation. Do not write that Down's is caused by polyploidy; an extra single chromosome is aneuploidy.