Human Genetics I: The Methods of Study, Cytogenetics from the Cell Cycle and Karyotyping to Banding, Chromosomal Abnormalities, FISH, the Lyon Hypothesis, Telomeres and Centromeres, Linkage, Chromosome Mapping and Genomic Imprinting, the Modes of Inheritance, and Dermatoglyphics with Dankmeijer's, Furuhata's and the Pattern Intensity Indices Worked

The cell cycle runs through interphase — G1 (growth), S (DNA synthesis, each chromosome replicated into two chromatids) and G2 — and then M, mitosis (prophase, metaphase, anaphase, telophase) with cytokinesis; non-dividing cells rest in G0, and checkpoints at G1/S, G2/M and the spindle guard against damaged or unreplicated DNA. Meiosis, in the germ line, has two divisions and produces haploid gametes, with crossing-over in prophase I. A karyotype is the ordered display of a cell's chromosomes photographed at metaphase, when they are most condensed: 46 in humans (Tjio and Levan, 1956, correcting Painter's 48), 22 pairs of autosomes arranged by size and centromere position into groups A–G under the Denver (1960) system, plus XX or XY. Banding, introduced around 1970, made each chromosome identifiable: Q-banding (Caspersson, 1970) stains with quinacrine mustard and reads bright fluorescent bands under ultraviolet light; G-banding (Seabright, 1971) treats with trypsin and stains with Giemsa, giving dark bands in AT-rich, gene-poor regions — the routine clinical method, described in the Paris (1971) nomenclature by arm (p short, q long), region and band, e.g. 5p15; C-banding (Arrighi and Hsu, 1971) stains only the constitutive heterochromatin around centromeres and on the Y; R-banding is the reverse of G. Fluorescence in situ hybridisation (FISH, 1980s) hybridises a fluorescent DNA probe to a specific sequence on the chromosome and lights it up, allowing microdeletions, translocations and gene positions to be seen in metaphase or interphase nuclei; chromosome painting and comparative genomic hybridisation extend it. Mary Lyon's hypothesis (1961) states that in every female somatic cell one of the two X chromosomes is inactivated early in development, at random, and that the inactive X persists as the Barr body (Barr and Bertram, 1949) — so females are mosaics for X-linked genes (the tortoiseshell cat), dosage is equalised with males, and the number of Barr bodies is one less than the number of X chromosomes (0 in XY and XO, 1 in XX and XXY, 2 in trisomy X). Telomeres are the repeated TTAGGG sequences capping the chromosome ends (Muller coined the term, 1938); they shorten at each division, setting the Hayflick limit of about 50 divisions, and are rebuilt by telomerase in germ and cancer cells (Blackburn, Greider and Szostak, Nobel 2009). The centromere, the primary constriction, carries the kinetochore to which spindle fibres attach and holds the sister chromatids together; its position classifies chromosomes as metacentric, submetacentric, acrocentric (13, 14, 15, 21, 22, with satellites) or telocentric.

Genes on the same chromosome tend to be inherited together — linkage, discovered by Morgan in Drosophila (1910–11), the exception to Mendel's independent assortment. Crossing-over in meiosis separates linked genes in proportion to the distance between them, so the recombination fraction is a measure of distance: Sturtevant drew the first genetic map in 1913, and one map unit, the centimorgan (cM), is 1% recombination (the human genome is about 3,500 cM across some 3,000 million base pairs, roughly 1 cM per million bases). In humans linkage was first shown between colour blindness and haemophilia on the X (Bell and Haldane, 1937), and pedigree linkage is tested by Morton's LOD score (1955), the log10 of the odds of linkage at a given recombination fraction against no linkage; a LOD of 3 or more (odds of 1,000 : 1) is accepted as linkage and −2 as exclusion. Mapping progressed from linkage maps through somatic-cell hybrids (1960s–70s), in situ hybridisation and restriction maps to physical maps of cloned DNA and finally the Human Genome Project's sequence (draft 2001, completed 2003; the last gaps closed in 2022). Genomic imprinting is the exception to Mendel's other assumption, that a gene acts the same whichever parent it came from: some genes are silenced by methylation in the sperm or the egg, so that only the maternal or only the paternal copy is expressed. Surani's mouse experiments (1984) showed that embryos with two maternal or two paternal genomes fail. The human demonstration is a pair of syndromes from the same deletion at 15q11–q13: inherited from the father it gives Prader–Willi syndrome (obesity, hypotonia, small hands), from the mother Angelman syndrome (seizures, absent speech, a happy demeanour); uniparental disomy of chromosome 15 produces the same pair. IGF2 (paternally expressed) and H19 (maternally expressed) are the classic imprinted pair, and Beckwith–Wiedemann syndrome their disturbance.

Dermatoglyphics (Cummins and Midlo coined the word in 1926; their Finger Prints, Palms and Soles of 1943 is the standard text) is the study of the epidermal ridges of the fingers, palms and soles, which form between the tenth and sixteenth weeks of fetal life, never change thereafter and are polygenic — total ridge count has a heritability near 0.9 (Holt). Galton (Finger Prints, 1892) fixed the three basic finger-ball patterns: the arch (ridges pass from side to side; no triradius; the tented arch has a rudimentary one), the loop (ridges enter and return on the same side around one triradius; ulnar loops open toward the little finger and are the commonest pattern, radial loops toward the thumb) and the whorl (concentric or spiral ridges with two triradii; including central-pocket, double-loop and accidental forms). Roughly, in most populations, loops make 60–65%, whorls 25–35% and arches 5% of fingers. Three population indices summarise the frequencies. Dankmeijer's index = (arches ÷ whorls) × 100. Furuhata's index = (whorls ÷ loops) × 100. Cummins's pattern intensity index counts triradii — 0 for an arch, 1 for a loop, 2 for a whorl — so for an individual it is simply the total number of triradii on the ten fingers (0 to 20), and for a sample PII = (2W + L) ÷ N, where W and L are the total whorls and loops and N the number of individuals; with percentage frequencies it is (2 × W% + L%) ÷ 10, the mean number of triradii per person. Worked: a woman has 2 arches, 5 loops and 3 whorls. Dankmeijer = 2 ÷ 3 × 100 = 66.7; Furuhata = 3 ÷ 5 × 100 = 60.0; her pattern intensity = 2 × 3 + 5 = 11 triradii. Worked for a sample: among 200 people (2,000 fingers) there are 100 arches (5%), 1,300 loops (65%) and 600 whorls (30%). Dankmeijer = 100 ÷ 600 × 100 = 16.7; Furuhata = 600 ÷ 1,300 × 100 = 46.2; PII = (2 × 600 + 1,300) ÷ 200 = 2,500 ÷ 200 = 12.5, the same as (2 × 30 + 65) ÷ 10.

Ridge counts add quantity to pattern. A finger's ridge count is the number of ridges crossed by a straight line from the triradius to the core (an arch counts 0; a whorl has two triradii and two counts). The total finger ridge count (TFRC) sums, over the ten fingers, the count of each finger taking the larger of a whorl's two counts (mean about 145 in males and 127 in females in European samples; lower in Down syndrome, higher in Turner syndrome); the absolute finger ridge count (AFRC) sums both counts of every whorl and so exceeds TFRC in whorl-rich hands. On the palm, four digital triradii a, b, c and d lie at the bases of the index to little fingers, and an axial triradius t lies near the wrist; the main lines A, B, C and D radiate from the digital triradii and end in one of 13 numbered regions round the palm's border. The palmar formula records where each main line ends, written in the order D.C.B.A with the position of t, for example 11.9.7.5.t — a high D and A give a transverse course. Cummins's main-line index is the sum of the numerical values of the terminations of lines D and A; the higher the index, the more transverse the ridges — this is what "transversality" means, and it is greater on the right hand and in some populations. The atd angle is measured at t between lines drawn to a and d: about 45° in normal adults, rising as t moves distally (t′, t″), and exceeding about 57° in Down syndrome; it decreases with age as the palm grows. Flexion creases are not ridges but the folds of the palm: the distal and proximal transverse creases and the thenar (radial longitudinal) crease; their fusion into a single transverse palmar crease — the "simian crease" — occurs in about 1% of the general population and in about half of people with Down syndrome, while the Sydney line is a proximal crease that runs the full width. Dermatoglyphic frequencies vary between populations and are inherited, so anthropologists have used them, alongside blood groups, to compare castes, tribes and regions; arches and radial loops are rarer and whorls commoner in East Asian than in European samples, and Indian tribal groups have been extensively surveyed by S.S. Sarkar and others.