Chromosomal Aberrations: Down, Turner, Klinefelter, Imprinting and Genetic Counselling

9.4 Chromosomes and chromosomal aberrations in man, methodology. (a) Numerical and structural aberrations (disorders). (b) Sex chromosomal aberrations – Klinefelter (XXY), Turner (XO), Super female (XXX), intersex and other syndromic disorders. (c) Autosomal aberrations – Down syndrome, Patau, Edward and Cri-du-chat syndromes. (d) Genetic imprints in human disease, genetic screening, genetic counseling, human DNA profiling, gene mapping and genome study.

Official Syllabus: Paper I, Unit 9.4

Unit 1.7 described what a chromosome is, and Unit 9.1 how a karyotype is made: blood cells are grown, stopped at metaphase with colchicine, G-banded and arranged in 23 pairs, and written as 46,XY. This unit asks what happens when that picture is wrong (a chromosome too many, one too few, or a broken piece), then follows the uses of this knowledge: screening, counselling, DNA profiling and genome mapping.

1. Chromosomes and the Language of Aberrations

A baby in a district hospital has low muscle tone, a flat face and a single crease across each palm. The karyotype reads 47,XY,+21: a boy with 47 chromosomes, the extra one a chromosome 21, the cause of Down syndrome. Reading such reports needs four ideas.

• Autosomes and sex chromosomes: 22 pairs of autosomes (chromosomes not involved in sex determination) plus XX or XY. The SRY gene (sex-determining region of Y) on Yp turns the embryonic gonad into a testis; without it an ovary forms. So a person with a Y is usually male whatever the number of X chromosomes.
• Centromere position: metacentric (central), submetacentric (off-centre) or acrocentric (near one end: 13, 14, 15, 21, 22); sorted by size into groups A to G (Denver system, 1960).
• Arms and bands: the short arm is p and the long arm q. 1q23 means chromosome 1, long arm, region 2, band 3; bands are numbered outward from the centromere.
• ISCN notation (International System for Human Cytogenomic Nomenclature): number of chromosomes, sex chromosomes, then the change: 47,XX,+21 (trisomy 21), 45,X (Turner), 46,XY,del(5p) or 46,XY,5p− (cri-du-chat), 45,XX,t(14;21) (balanced translocation carrier), 46,XX/47,XX,+21 (a mosaic: two cell lines in one person).

1.1 X-inactivation and the Barr body

The British-Canadian anatomists Murray Barr and Ewart Bertram (1949) saw a dark spot, the sex chromatin or Barr body, in the nuclei of female cells only. The English geneticist Mary Lyon (1961) explained it: in every female cell one X is switched off early in development, at random, and condensed into the Barr body (the Lyon hypothesis).

• Rule: number of Barr bodies = number of X chromosomes − 1. Turner (45,X) has none; Klinefelter (47,XXY) has one; 47,XXX has two.
• Why it matters: because extra X chromosomes are silenced, sex-chromosome aneuploidy is far milder than autosomal aneuploidy; symptoms come from the few genes that escape inactivation (such as SHOX, for height).

1.2 Methodology in brief

The laboratory methods were explained in Unit 9.1. The table recalls which method suits which kind of aberration.

Method	What it sees	Best for
Karyotype with G-banding (Giemsa)	Whole chromosomes, about 400–550 bands	Aneuploidy, large deletions and translocations (above about 5–10 million bases)
Q, R, C, NOR, T banding	Quinacrine fluorescence and other stains	Y (Q), chromosome ends (R, T), heterochromatin (C)
FISH (fluorescence in situ hybridisation)	One DNA sequence lit by a fluorescent probe	Microdeletions (22q11.2, 15q11–q13); rapid counting of 13, 18, 21, X, Y in uncultured cells
Chromosomal microarray (array CGH)	Gains and losses across the genome	Small copy-number changes; first test for unexplained developmental delay
NIPT (non-invasive prenatal testing)	Fetal DNA fragments in the mother’s blood	Screening for trisomies 21, 18, 13

Each newer method sees smaller changes, but only the karyotype shows how material is arranged: a balanced translocation, with nothing gained or lost, is invisible to a microarray.

2. Numerical Aberrations

2.1 Types

The terms describe whether whole sets or single chromosomes are affected. Heteroploidy is the general word for any change in number.

Term	Meaning	Human example
Euploidy	Exact multiples of the set (n = 23)	Diploid 2n = 46 is normal
Polyploidy	Extra whole sets	Triploidy (69,XXY) and tetraploidy (92): found in miscarriages and partial molar pregnancies; not compatible with long survival
Aneuploidy	One or a few chromosomes extra or missing	Trisomy (2n+1: 47,+21), monosomy (2n−1: 45,X), tetrasomy (2n+2: 48,XXXY); nullisomy (2n−2) is lethal

Chromosome errors are common: about half of first-trimester miscarriages carry one, so natural selection removes most before birth.

2.2 Non-disjunction: the main mechanism

Non-disjunction is the failure of a chromosome pair (meiosis I) or of sister chromatids (meiosis II) to separate at anaphase.

• In meiosis I: both homologues go to one pole, giving two n+1 and two n−1 gametes.
• In meiosis II: one secondary cell is affected, giving one n+1, one n−1 and two normal gametes.
• Fertilisation of an n+1 gamete by a normal one gives a trisomic zygote (47); of an n−1 gamete, a monosomic zygote (45).
• Mitotic non-disjunction after fertilisation gives mosaicism, usually with milder features because only some cells are abnormal.
• Anaphase lag (a chromosome left behind on the spindle and lost) is a second cause of monosomy, common in Turner syndrome.
• Primary and secondary non-disjunction: the first arises in normal parents; the second occurs when a parent already trisomic (or carrying a translocation) passes on the error.

2.3 The maternal age effect

A woman’s oocytes (egg cells) begin meiosis before her own birth and pause in prophase I for 15 to 45 years until ovulation. Over these decades the cohesin proteins holding paired chromosomes weaken, so pairs separate wrongly more often; sperm, by contrast, are made continuously. Hence about 90 per cent of trisomy 21 arises in maternal meiosis, mostly meiosis I, and risk rises steeply with age (§4.1).

Why only a few aneuploidies survive to birth: monosomy of any autosome is lethal in the embryo. Only trisomies of 13, 18 and 21, the chromosomes carrying the fewest genes, reach term, along with the sex-chromosome aneuploidies, which X-inactivation softens. Severity follows gene content: trisomy 21 (fewest genes) is compatible with a long life, trisomy 13 and 18 rarely with one year.

3. Sex-Chromosome Aberrations

The four commonest sex-chromosome aneuploidies are compared below; the text after the table explains each.

Feature	Klinefelter	Turner	Triple X	XYY
Karyotype	47,XXY	45,X (XO)	47,XXX	47,XYY
Described	Klinefelter 1942; karyotype Jacobs and Strong 1959	Turner 1938; karyotype Ford 1959	Jacobs 1959	Sandberg 1961; Jacobs 1965 survey
Frequency	1 in 500–1,000 males	1 in 2,000–2,500 females	About 1 in 1,000 females	About 1 in 1,000 males
Barr bodies	1	0	2	0
Phenotype	Male; tall, small testes, sterile	Female; short, streak ovaries, sterile	Female; tall, usually fertile	Male; tall, usually fertile
Intellect	Usually normal; language delay common	Usually normal; spatial difficulties	Normal to mildly lower	Normal to mildly lower

3.1 Klinefelter syndrome (47,XXY)

• History: described by the American physician Harry Klinefelter (1942, with Reifenstein and Albright, Boston); the extra X was shown by Patricia Jacobs and John Strong (1959).
• Origin: non-disjunction in either parent (about half paternal: an XY sperm; half maternal: an XX egg), so maternal age matters less than in Down syndrome.
• Features: hypogonadism (small testes, low testosterone, high FSH and LH), azoospermia (no sperm), gynaecomastia (breast development), sparse body hair, long legs and tall stature; higher risk of male breast cancer and osteoporosis. Taurodontism (enlarged pulp chambers in the molars) is frequent.
• Variants: 48,XXXY, 48,XXYY and 49,XXXXY are more severe, intellectual disability rising with each extra X; mosaics (46,XY/47,XXY) are milder, sometimes fertile.
• Management: testosterone from puberty, speech support; sperm retrieval with IVF lets some men father children.

3.2 Turner syndrome (45,X)

• History: described by the American endocrinologist Henry Turner (1938); the missing X shown by Charles Ford and colleagues (1959).
• Survival: about 99 per cent of 45,X conceptions miscarry, so survivors are often mosaics.
• Karyotypes: about half are 45,X; the rest are mosaics (45,X/46,XX), an isochromosome Xq (two long arms, no short arm) or a ring X.
• Features: short stature (loss of one SHOX gene on Xp), webbed neck, low hairline, shield chest with widely spaced nipples, streak ovaries and primary amenorrhoea, coarctation of the aorta, kidney anomalies; intelligence usually normal.
• Why the short arm matters: loss of part of Xp gives short stature; loss of part of Xq gives ovarian failure with normal height: stature genes lie on Xp, ovarian genes on both arms.
• Management: growth hormone in childhood, oestrogen at puberty, cardiac follow-up.

3.3 Triple X (47,XXX) and XYY (47,XYY)

• Triple X: the old name “super female” is a misnomer: most women are tall and of normal appearance and fertility, with a modest risk of learning and speech difficulty. 48,XXXX and 49,XXXXX are more severe.
• XYY: arises from non-disjunction in the father’s meiosis II. Patricia Jacobs (1965) found it more often in a Scottish secure hospital, and the press called it the “criminal chromosome“. A Danish population study (Witkin and colleagues, 1976) found no link with violence; a slight excess of convictions tracked lower average IQ. It is a warning against reading behaviour from chromosomes.

3.4 Intersex and differences of sex development

Intersex describes people whose chromosomes, gonads and genitals do not fit the typical male or female pattern. Older texts used “true hermaphrodite” and “pseudohermaphrodite”; the Chicago Consensus (2006) replaced these with disorders (differences) of sex development (DSD). The table matches old terms to new.

Current category	Old term	Example and cause
46,XX DSD	Female pseudohermaphrodite	Congenital adrenal hyperplasia (21-hydroxylase deficiency, gene on chromosome 6): excess fetal androgen masculinises the genitals of an XX child
46,XY DSD	Male pseudohermaphrodite	Androgen insensitivity (receptor gene on X): an XY person with testes but a female body, because cells cannot respond to testosterone
Sex-chromosome DSD	Mixed gonadal dysgenesis	45,X/46,XY mosaic: one testis and one streak gonad
Ovotesticular DSD	True hermaphrodite	Both ovarian and testicular tissue, often 46,XX

• SRY shows the logic: an XX male carries SRY moved onto an X by an error at meiosis; an XY female (Swyer syndrome) has a mutated SRY. Sex follows the gene, not the chromosome count.
• India: the Madras High Court (Arunkumar v. Inspector General of Registration, April 2019) held that parental consent cannot stand in for a child’s consent and directed a ban on “sex-normalising” surgery on intersex infants; Tamil Nadu issued the order in August 2019, the first state to do so, except where life is threatened.

4. Autosomal Aberrations

4.1 Down syndrome (trisomy 21)

• History: the English physician John Langdon Down described it in 1866 and called it “mongolism“, believing the children resembled “Mongolian” people and represented a reversion to a “lower race”. Jérôme Lejeune (France, 1959) found the extra chromosome 21: the first chromosomal disorder identified in humans. After a 1961 letter by geneticists and a request from the Mongolian delegation, the WHO dropped the term in 1965: a clear case of a racial label being removed from medicine (Unit 9.5).
• Frequency: about 1 in 800–1,000 live births, roughly 30,000 births a year in India (Ministry of Social Justice, 2018). Because younger women have most babies, most affected children are born to mothers under 35.
• Features: hypotonia (low muscle tone), flat face, upward-slanting eyes with epicanthic folds, small ears, protruding tongue, short broad hands, single palmar (“simian”) crease, gap between first and second toes, mild to moderate intellectual disability; congenital heart defects in about half, duodenal atresia, leukaemia, thyroid disease and early Alzheimer changes (the APP gene lies on chromosome 21).
• Dermatoglyphics: excess ulnar loops and a distal axial triradius (t″).
• Life expectancy: older sources give 16 years, but with heart surgery and care it now reaches about 60 years.

Three cytogenetic types. The type matters because it decides the risk to the next child.

Type	Share	Mechanism	Recurrence
Free trisomy 21 (47,+21)	About 95%	Non-disjunction, mostly maternal meiosis I	Low; rises with maternal age
Robertsonian translocation (46,t(14;21) or t(21;21))	About 3–4%	Extra 21q fused to chromosome 14 or 21; often inherited from a balanced carrier parent with 45 chromosomes	About 10–15% if the mother carries t(14;21), lower if the father; 100% for t(21;21)
Mosaic (46/47,+21)	About 1–2%	Mitotic error after fertilisation	Low; features often milder

So when a child has translocation Down syndrome, the parents are karyotyped: a healthy carrier can have further affected children at any age.

Mother’s age	Approximate risk at birth
20–25	1 in 1,400
30	1 in 900
35	1 in 350
40	1 in 100
45	1 in 30

4.2 Patau, Edwards and cri-du-chat syndromes

The three rarer syndromes are compared in one table; all are diagnosed by karyotype and offered prenatal diagnosis in the next pregnancy.

Feature	Patau	Edwards	Cri-du-chat
Karyotype	47,+13	47,+18	46,5p− (deletion)
Described	Klaus Patau, 1960	John H. Edwards, 1960	Jérôme Lejeune, 1963
Frequency	About 1 in 10,000–16,000	About 1 in 5,000–6,000	About 1 in 15,000–50,000
Key signs	Holoprosencephaly (undivided forebrain), cleft lip and palate, small eyes, polydactyly	Clenched fists with overlapping fingers, rocker-bottom feet, small jaw, heart defects	High-pitched cat-like cry (abnormal larynx), microcephaly (small head), wide-set eyes, intellectual disability
Survival	Most die in the first year	About 90% die in the first year	Often survives to adulthood

Why cri-du-chat differs: it is a structural error (a missing piece of 5p), not an extra chromosome, so the child lacks only some genes and can live long. About 10–15 per cent of cases come from a parent carrying a balanced translocation involving 5p, which is why parents are tested.

5. Structural Aberrations

5.1 How breaks arise

• Spontaneous: faulty DNA repair and unequal crossing over between similar repeated sequences, which is why the same microdeletions recur in unrelated people.
• Induced: ionising radiation, chemical mutagens and some viruses.
• Balanced vs unbalanced: in a balanced rearrangement no material is lost (inversions, most reciprocal translocations): carriers are healthy but have unbalanced gametes, causing miscarriage or an affected child. An unbalanced change causes disease directly.

5.2 The main types

Type	What happens	Example
Deletion	A segment is lost, terminal (end) or interstitial (middle); microdeletion if below microscope resolution	5p− cri-du-chat; 22q11.2 DiGeorge syndrome; 15q11–q13 Prader-Willi and Angelman
Duplication	A segment is doubled, tandem (ABC-ABC) or reverse (ABC-CBA)	17p12 duplication in Charcot-Marie-Tooth neuropathy; duplication also creates new gene families (globins) in evolution
Inversion	A segment turns 180°: paracentric (centromere outside) or pericentric (centromere inside)	inv(9), a harmless variant; pericentric inversions distinguish human and chimpanzee chromosomes
Reciprocal translocation	Two non-homologous chromosomes exchange segments	Philadelphia chromosome t(9;22) in chronic myeloid leukaemia; t(8;14) in Burkitt lymphoma
Robertsonian translocation	Two acrocentric chromosomes (13, 14, 15, 21, 22) fuse at the centromere; short arms lost	t(14;21) carrier with 45 chromosomes; about 1 in 1,000 people
Ring chromosome	Both ends break and join	Ring X in Turner; ring 13
Isochromosome	The centromere divides crosswise, giving two identical arms	i(Xq) in Turner syndrome

• Inversion loops: in an inversion carrier the paired chromosomes form a loop at meiosis; a crossover inside it gives dicentric and acentric products (paracentric) or duplicated and deleted products (pericentric), which is why carriers have more miscarriages.
• Translocation and cancer: the Philadelphia chromosome, found by Peter Nowell and David Hungerford (1960), joins BCR to the ABL gene, creating a fused gene that drives cell division: an activated oncogene (a gene whose overactivity causes cancer). The drug imatinib, which blocks the fused protein, was the first cancer treatment designed against a chromosomal change.
• Evolution: human chromosome 2 arose by the fusion of two ape chromosomes (great apes have 48), and several pericentric inversions separate human and chimpanzee chromosomes: structural change is also a source of evolution, not only disease.

6. Genetic Imprints in Human Disease

Two children both lack the same small piece of chromosome 15 (15q11–q13). One is floppy at birth, later eats compulsively, becomes obese and has small genitals: Prader-Willi syndrome. The other has severe intellectual disability, seizures, jerky movements and frequent laughter: Angelman syndrome. The only difference is that the first child’s deletion is on the chromosome from the father, the second’s on the one from the mother. This is genomic imprinting.

6.1 Concept and mechanism

• Mendel’s assumption broken: Mendel’s reciprocal crosses (tall female × dwarf male and the reverse) gave identical results, so classical genetics assumed parental equivalence. Imprinting is the exception: a gene’s expression depends on its parent of origin.
• Mechanism: DNA methylation (adding methyl groups to cytosine) and histone changes at an imprinting control region silence one parental copy. The mark is epigenetic: it changes gene activity, not the DNA sequence.
• Life cycle: marks are erased in the germ cells of each new generation and reset according to the sex of that individual, so a man passes paternal marks on all his chromosomes, including those from his mother.
• Scale: only about 100–200 of some 20,000 human genes are imprinted, and imprinting varies between species.
• Discovery: mouse embryos with two maternal or two paternal genomes failed to develop (McGrath and Solter; Surani, 1984). In humans a hydatidiform mole (two paternal sets) is placenta without embryo; an ovarian teratoma (two maternal sets) is tissue without placenta.
• Why imprinting exists (conflict theory): the American biologist David Haig argued that paternal genes favour drawing more maternal resources into the fetus (growth-promoting IGF2 is paternally expressed), while maternal genes restrain growth to spread resources over all her children.

6.2 Imprinting disorders

Each disorder arises in more than one way; what they share is the loss of the active parental copy.

Disorder	Region	Usual mechanisms	Main features
Prader-Willi	15q11–q13: paternal genes (SNRPN, NDN, MAGEL2) lost	Paternal deletion (about 70%); maternal uniparental disomy (both 15s from mother, about 25%); imprinting defect	Neonatal hypotonia, hyperphagia and obesity, hypogonadism, short stature
Angelman	15q11–q13: maternal UBE3A lost in brain	Maternal deletion (about 70%); paternal disomy; UBE3A mutation; imprinting defect	Severe intellectual disability, absent speech, seizures, ataxia, happy demeanour
Beckwith–Wiedemann	11p15: excess IGF2	Paternal disomy or methylation change	Overgrowth, large tongue, Wilms tumour risk
Silver–Russell	11p15 (or 7)	Loss of paternal methylation	Growth restriction, triangular face

• Uniparental disomy (both copies of a chromosome from one parent) arises when a trisomic embryo loses the extra chromosome (“trisomy rescue“): a normal chromosome count can still cause an imprinting disease.
• Cancer: loss of imprinting of IGF2 occurs in Wilms tumour; reduced expression of the paternally expressed DIRAS3 is reported in many ovarian and breast cancers.
• Hereditary paraganglioma (glomus tumour, SDHD gene) appears almost only when the mutation comes from the father.

7. Genetic Screening

7.1 Principles and types

Screening sorts people into higher and lower risk; diagnosis confirms. The WHO principles of Wilson and Jungner (1968) require an important condition with a known natural history, a valid, acceptable test, an effective treatment or choice, and justified cost. A test is judged by sensitivity (true cases detected) and specificity (unaffected correctly reassured).

Type	Who is tested	Examples
Carrier (heterozygote) screening	Communities with high carrier frequency	Tay-Sachs among Ashkenazi Jews; thalassaemia in Cyprus, Sardinia and India; sickle cell in tribal India (Unit 9.1)
Prenatal screening	Pregnant women	First-trimester combined test (nuchal translucency on ultrasound plus PAPP-A and hCG in serum), quadruple test, NIPT; maternal serum alpha-fetoprotein for neural tube defects
Prenatal diagnosis	Screen-positive or high-risk pregnancies	Chorionic villus sampling (10–13 weeks), amniocentesis (15–20 weeks), cordocentesis (umbilical cord blood); karyotype, FISH or DNA test
Preimplantation genetic testing	Couples using IVF	Testing embryos before transfer
Newborn screening	All newborns	Heel-prick blood spot (Guthrie, 1963, for phenylketonuria); congenital hypothyroidism, G6PD deficiency, galactosaemia
Predictive testing	Adults with a family history	BRCA1/BRCA2 for breast and ovarian cancer; Huntington disease

• Why carrier screening works best in defined communities: recessive disorders are common where endogamy keeps carriers marrying carriers. The Cyprus programme, backed from 1983 by a premarital certificate, reduced thalassaemia-major births to near zero. Reich and colleagues (2009) predicted that India’s many endogamous groups would each carry their own excess of recessive disease (Unit 9.5).
• Why newborn screening pays: a diet started early prevents disability in phenylketonuria, and a daily thyroxine tablet does so in congenital hypothyroidism.

7.2 Indian framework

• PCPNDT Act, 1994 (Pre-Conception and Pre-Natal Diagnostic Techniques (Prohibition of Sex Selection) Act; in force 1996, renamed and strengthened 2003):
  • s.3: only registered genetic counselling centres, laboratories and clinics may conduct prenatal diagnosis; s.3A prohibits sex selection.
  • s.4(2): prenatal tests are allowed only to detect chromosomal abnormalities, genetic metabolic diseases, haemoglobinopathies, sex-linked genetic diseases and congenital anomalies.
  • s.4(3): a test needs one of these recorded conditions: mother above 35 years, two or more spontaneous abortions or fetal loss, exposure to teratogens (drugs, radiation, infection, chemicals), or a family history of mental retardation, physical deformity or genetic disease.
  • s.5: written consent is required, and the sex of the fetus may not be communicated by words, signs or any other method.
• Why the law exists: the same amniocentesis that detects Down syndrome also reveals fetal sex, and its misuse for sex-selective abortion lowered India’s child sex ratio to 918 girls per 1,000 boys (Census 2011). The Act keeps diagnosis available while blocking sex determination.
• MTP (Amendment) Act, 2021: termination beyond 24 weeks is permitted for substantial fetal abnormalities diagnosed by a Medical Board, which makes late prenatal diagnosis meaningful.
• Rashtriya Bal Swasthya Karyakram (2013) screens children for the “4 Ds” (defects at birth, diseases, deficiencies, developmental delays), including Down syndrome; universal newborn biochemical screening exists only in some states.

8. Genetic Counselling

8.1 Definition and aims

The term was coined by the American geneticist Sheldon Reed (1947). The American Society of Human Genetics (committee chaired by F. Clarke Fraser, 1975) defined it as “a communication process which deals with the human problems associated with the occurrence, or the risk of occurrence, of a genetic disorder in a family.” Its aims are to help the family understand the diagnosis, the inheritance and recurrence risk, the options, and to make and adjust to a decision.

8.2 Steps

1. Referral and intake: an affected child, recurrent miscarriage, infertility, consanguinity, an abnormal screen or disputed paternity.
2. Pedigree: at least three generations, recording consanguinity, miscarriages and deaths (Unit 9.1).
3. Diagnosis: examination and tests (karyotype, FISH, biochemical or DNA); without a firm diagnosis the risk figures may be wrong.
4. Risk assessment: Mendelian (both parents carriers: 1 in 4 affected; dominant: 1 in 2), empirical (observed recurrence for multifactorial conditions such as cleft lip, about 3–4 per cent after one affected child) or Bayesian (combining prior risk with test results).
5. Communication of options: prenatal diagnosis, preimplantation testing, donor gametes, adoption, or accepting the risk.
6. Decision and support: non-directive counselling (the counsellor does not tell the family what to choose); psychosocial support and referral to support groups.
7. Follow-up: testing of relatives (cascade screening), and updates as knowledge changes.

Why non-directiveness matters: genetic counselling grew in the shadow of eugenics (Unit 12), when states decided who should reproduce. Respect for autonomy separates counselling from eugenic control.

8.3 Problems

• Mistaken paternity revealed by testing; confidentiality versus the relatives’ interest in knowing their own risk.
• Discrimination by employers and insurers: the US Genetic Information Nondiscrimination Act (2008) is one response.
• Uncertainty: distinguishing a harmless polymorphism from a disease variant (a “variant of uncertain significance”).
• Cultural context: in South India, where cousin and uncle–niece marriage is a valued kinship preference, counselling must give the higher recessive risk without condemning the custom.
• Misuse: sex selection; pressure to terminate; the lingering eugenic idea that carriers should not marry. Recessive alleles hide in heterozygotes, so even preventing all affected births lowers their frequency only slowly.

8.4 Gene therapy

• Somatic therapy changes the patient’s own cells; germ-line therapy (embryo editing) would change descendants and is banned in most countries; the gene-edited twins born in China (He Jiankui, 2018) were widely condemned.
• Milestones: first approved trial for ADA deficiency (US, 1990); the CRISPR therapy Casgevy for sickle-cell disease and beta-thalassaemia (UK and US, 2023).

9. Human DNA Profiling

The principle, PCR and the logic of paternity testing were explained in Unit 9.1 (§8.4): a child carries one allele at each locus from each parent, so an alleged father lacking the child’s paternal allele at several loci is excluded. Here the methods and their limits are compared.

Method	Marker	Strength	Limit
RFLP–VNTR (Alec Jeffreys, 1984)	Minisatellites (10–100 base repeats), cut by restriction enzymes, separated by electrophoresis, Southern blot, radioactive probe	Highly variable	Needs much fresh DNA; slow
PCR–STR (since the 1990s)	Microsatellites (2–6 base repeats) at 15–24 standard loci	Works on traces and old samples; standard databases	Mixtures and contamination
Y-STR	Y chromosome	Male line; sexual-assault mixtures	Shared by all paternal relatives
Mitochondrial DNA	Maternal line	Hair shafts, bones	Shared by all maternal relatives

• Probability, not certainty: a match is reported as a random match probability from allele frequencies in a reference population; because frequencies differ between populations, the database matters, and grouping people by “race” for it raises the questions of Unit 9.5.
• India: DNA fingerprinting was developed at CCMB, Hyderabad, by Lalji Singh (1988); the Centre for DNA Fingerprinting and Diagnostics (CDFD) followed. The DNA Technology (Use and Application) Regulation Bill, 2019, which proposed a national DNA data bank, was withdrawn on 24 July 2023, the government stating that the Criminal Procedure (Identification) Act, 2022, which allows biological samples to be taken as “measurements”, covers most of it. Critics note the loss of the Bill’s safeguards: accreditation of laboratories, quality standards and rules on deleting profiles.

10. Gene Mapping and Genome Study

From 1979 the American psychologist Nancy Wexler collected blood from a huge family around Lake Maracaibo, Venezuela, in which Huntington disease was common. By following DNA markers through this pedigree, James Gusella and colleagues (1983) placed the gene on chromosome 4; the gene itself was isolated in 1993. This is gene mapping by linkage: a marker that travels with the disease through a family must lie close to the gene.

10.1 Kinds of maps and methods

Map	Unit	Built by
Genetic (linkage) map	Centimorgan (1% recombination)	Following markers through families; LOD score (likelihood of linkage, Newton Morton, 1955)
Cytogenetic map	Chromosome bands	Banding, FISH, somatic-cell hybrids (human–mouse cells that lose human chromosomes)
Physical map	Base pairs	Restriction fragments, cloned overlapping fragments (contigs)
Sequence map	Individual bases	DNA sequencing

• Genome-wide association studies (GWAS): instead of following families, a GWAS compares hundreds of thousands of SNPs in thousands of patients and controls and looks for variants more common in patients (significance threshold p < 5 × 10⁻⁸). The first notable success found a complement factor H variant in age-related macular degeneration (2005); the Wellcome Trust Case Control Consortium (2007) studied seven common diseases at once.
• What GWAS taught: common diseases (diabetes, heart disease, schizophrenia) are polygenic, each variant adding a tiny risk, hence polygenic risk scores. Limits: hits explain little of the heritability (“missing heritability“), and most samples are European, so results transfer poorly to Indians.

10.2 The Human Genome Project

• Origin: the US Department of Energy sought better ways to detect mutations in Hiroshima and Nagasaki survivors (Alta, Utah, 1984); a National Research Council report (1988) proposed sequencing the genome with the National Institutes of Health; HUGO (1988) coordinated internationally.
• Course: launched October 1990 as a 15-year, US$3 billion effort led first by James Watson; joined by the UK (Sanger Centre), France, Germany, Japan and China; a private rival, Celera Genomics (Craig Venter), sped it up. The draft was announced on 26 June 2000 and published in February 2001; the project was declared complete in April 2003.
• Goals: map and sequence the 3 billion base pairs; identify all genes; store data publicly; develop analysis tools; address ethical, legal and social implications (ELSI, set up 1990).
• Findings: only about 20,000 protein-coding genes (earlier estimates were 100,000); under 2 per cent of the genome codes for protein; any two people are about 99.9 per cent identical.
• Completion: the Telomere-to-Telomere consortium filled the last gaps (2022), and a pangenome of 47 people from diverse ancestries (2023) replaced the single mosaic reference.
• Criticism: “big science” diverting funds from small projects; most of the genome dismissed as junk (much is now known to regulate genes); privacy, genetic discrimination and patenting; over-promised cures.

10.3 Genome study in India and anthropology

• IndiGen (CSIR, 2019): whole genomes of 1,029 Indians (1,008 announced in October 2019), with genome cards for clinically relevant variants.
• GenomeIndia (DBT): 10,074 genomes from 83 populations, data opened in January 2025 (Unit 9.1).
• Population history: genome data revealed the ANI–ASI mixture behind most Indian groups (Unit 9.5) and Neanderthal ancestry in all non-Africans (Svante Pääbo; Nobel Prize 2022).
• Applications: rare-disease diagnosis, carrier screening, pharmacogenomics (choosing drugs by genotype, such as testing for HLA-B*15:02 before the anti-epileptic carbamazepine), cancer genomics, forensic identification and tracing migrations.

Key Terms

Term	Meaning in simple words
Karyotype	A picture of a cell’s chromosomes arranged in pairs
Aneuploidy	One chromosome extra or missing
Polyploidy	One or more whole extra sets of chromosomes
Non-disjunction	Failure of chromosomes to separate when gametes form
Mosaicism	Two cell lines with different chromosomes in one person
Barr body	The switched-off X chromosome seen in female cells
SRY	The gene on Y that starts male development
Robertsonian translocation	Two acrocentric chromosomes joined at the centromere
Microdeletion	A deletion too small to see under the microscope
Genomic imprinting	A gene’s activity depending on which parent it came from
Uniparental disomy	Both copies of a chromosome inherited from one parent
Carrier screening	Testing healthy people for one copy of a recessive gene
NIPT	A blood test of the mother that screens the fetus’s DNA
Non-directive counselling	Counselling that informs but leaves the decision to the family
STR	A short DNA sequence repeated a variable number of times, used in profiling
GWAS	A study scanning the whole genome for variants linked to a disease

Contemporary Developments

• DNA Bill withdrawn (2023): the DNA Technology Regulation Bill, 2019 was withdrawn on 24 July 2023 because the Criminal Procedure (Identification) Act, 2022 already allows biological samples to be taken; its laboratory-accreditation and data-deletion safeguards lapsed with it.
• Gene editing reaches the clinic (2023): Casgevy, the first CRISPR therapy, was approved for sickle-cell disease and beta-thalassaemia, two disorders India screens for on a large scale.
• Complete and diverse references (2022–23): the gapless T2T genome and the first pangenome improved the detection of structural variants that older maps missed.
• GenomeIndia (2025): 10,074 Indian genomes from 83 populations opened to researchers, allowing community-specific carrier screening and reducing the European bias of GWAS.

Diagrams to Master

1. Topic map: chromosomes and methods → numerical, sex-chromosome, autosomal, structural → imprinting → screening, counselling, profiling, mapping.
2. Non-disjunction: meiosis I (all four gametes abnormal: two n+1, two n−1) vs meiosis II (one n+1, one n−1, two normal); trisomy and monosomy after fertilisation.
3. Sex-chromosome aneuploidies: 47,XXY / 45,X / 47,XXX / 47,XYY with Barr bodies (X − 1), frequency and features.
4. Down syndrome types: free trisomy 95%, t(14;21) 3–4%, mosaic 1–2%; maternal-age curve (1 in 350 at 35, 1 in 100 at 40).
5. Structural aberrations: lettered chromosome (A–G) showing deletion, duplication, inversion (para/peri), reciprocal and Robertsonian translocation, ring, isochromosome.
6. Imprinting at 15q11–q13: paternal genes (SNRPN, NDN) vs maternal UBE3A; paternal loss → Prader-Willi, maternal loss → Angelman.

Revision Grid

Scholar	Work (year)	Key idea
John Langdon Down	1866	Described the syndrome; racial label “mongolism”
Henry Turner	1938	Turner syndrome described
Harry Klinefelter	1942	Klinefelter syndrome described
Jérôme Lejeune	1959; 1963	Trisomy 21; cri-du-chat (5p−)
Ford; Jacobs and Strong	1959	45,X and 47,XXY
Patau; Edwards	1960	Trisomy 13; trisomy 18
Mary Lyon	1961	X-inactivation
Patricia Jacobs	1965	XYY survey; later “criminal” myth refuted
Wilson and Jungner	1968	WHO screening principles
Fraser (ASHG)	1975	Definition of genetic counselling
Gusella and colleagues	1983	Huntington gene mapped to chromosome 4
McGrath and Solter; Surani	1984	Imprinting shown in mouse embryos
Alec Jeffreys	1984	DNA fingerprinting
Haig and Westoby	1989	Parental conflict theory of imprinting
Human Genome Project	1990–2003	Human genome sequenced; about 20,000 genes