Chromosomal mutations: changes in structure and number

Mutations come in all sizes. Lesson 10 deals with changes to single genes, often a single base. This lesson deals with changes large enough to see under a microscope: whole chromosomes gained or lost, and segments deleted, duplicated, inverted or moved to another chromosome. Such changes are a major cause of miscarriage, birth differences and intellectual disability in humans, a driving force in cancer, and, over evolutionary time, a source of new genes and new species. They also produce characteristic genetic behavior, such as unexpected ratios and reduced fertility, that geneticists use to detect them.

Changes in chromosome number

Changes in number are of two kinds. Euploidy refers to changes in the number of whole chromosome sets: a diploid becomes triploid (3n), tetraploid (4n) or more generally polyploid. Aneuploidy refers to the gain or loss of individual chromosomes, so that the cell has one or a few chromosomes too many or too few.

Nondisjunction

Most aneuploidy arises from nondisjunction, the failure of chromosomes to separate properly during meiosis. If homologues fail to separate in meiosis I, all four products are abnormal: two carry both homologues (n + 1) and two carry neither (n − 1). If sister chromatids fail to separate in meiosis II, only the two products of that division are abnormal; the other two are normal. When an n + 1 gamete is fertilized by a normal gamete, the zygote is trisomic; an n − 1 gamete gives a monosomic zygote.

In humans, about 10 to 25 percent of fertilized eggs may be aneuploid, the large majority because of errors in the egg, and most of these pregnancies end in miscarriage, often before the pregnancy is recognized. Only a few aneuploidies are compatible with live birth: trisomies of the small, gene-poor chromosomes 13, 18 and 21, and changes in sex chromosome number. Monosomy of any autosome is lethal early in development, showing how sensitive development is to the dosage of many genes at once.

Sex chromosome aneuploidies are much milder than autosomal ones because of X inactivation (lesson 7): all X chromosomes beyond the first are inactivated, and the Y carries few genes. Many people with an extra X or Y never learn of it. The mildness of Turner syndrome is more surprising, and reflects the fact that a few genes escape X inactivation, so a single X is not quite enough.

Maternal age and Down syndrome

The risk of trisomy 21 rises steeply with maternal age, from roughly 1 in 1,500 at age 20 to about 1 in 350 at 35 and about 1 in 30 at 45. About 90 percent of cases arise from nondisjunction in the egg, most often in meiosis I. The likely cause is the long pause in prophase I described in lesson 6: the protein complexes (cohesins) that hold homologues and sister chromatids together are laid down before birth and are not replaced, and they gradually deteriorate. Paternal age has a much smaller effect on aneuploidy, though it matters more for new point mutations (lesson 10).

About 3 to 4 percent of Down syndrome cases are caused not by nondisjunction but by a Robertsonian translocation, in which the long arm of chromosome 21 is fused to another acrocentric chromosome, usually 14. A person carrying a balanced translocation has 45 chromosomes but a normal amount of genetic material and is healthy, yet has a substantial chance of producing gametes with an extra copy of the 21q arm. Unlike most cases, translocation Down syndrome can recur in a family regardless of the mother's age, which is why a karyotype is recommended for every child diagnosed.

from itertools import combinations
# Gametes from a balanced Robertsonian carrier of a 14;21 fusion.
# The carrier has: normal 14, normal 21, and the fused chromosome t(14;21).
chroms = {"14": {"14": 1}, "21": {"21": 1}, "t(14;21)": {"14": 1, "21": 1}}
# Segregation sends one or two of the three chromosomes to each gamete (simplified: all
# six ways of splitting the trivalent into two poles treated as equally likely).
outcomes = []
items = list(chroms)
for k in (1, 2):
    for gam in combinations(items, k):
        dose = {"14": 0, "21": 0}
        for c in gam:
            for arm, n in chroms[c].items():
                dose[arm] += n
        partner = {"14": 1, "21": 1}          # normal gamete from the other parent
        zyg = {a: dose[a] + partner[a] for a in dose}
        if zyg == {"14": 2, "21": 2}:
            result = "balanced carrier" if "t(14;21)" in gam else "normal"
        elif zyg["21"] == 3: result = "translocation trisomy 21"
        elif zyg["21"] == 1: result = "monosomy 21 (lethal)"
        elif zyg["14"] == 3: result = "trisomy 14 (lethal)"
        else: result = "monosomy 14 (lethal)"
        outcomes.append((" + ".join(gam), result))
for gam, res in outcomes:
    print(f"gamete {gam:16s} -> zygote: {res}")

gamete 14               -> zygote: monosomy 21 (lethal)
gamete 21               -> zygote: monosomy 14 (lethal)
gamete t(14;21)         -> zygote: balanced carrier
gamete 14 + 21          -> zygote: normal
gamete 14 + t(14;21)    -> zygote: trisomy 14 (lethal)
gamete 21 + t(14;21)    -> zygote: translocation trisomy 21

In reality the segregations are not equally likely: the alternate pattern that gives normal and balanced gametes is favored, and many unbalanced embryos are lost early. Observed risks of a liveborn child with Down syndrome are about 10 to 15 percent when the mother carries the translocation and about 1 percent when the father does.

Prenatal screening and diagnosis

Screening tests estimate the chance that a pregnancy has a chromosome change; diagnostic tests give a definite answer. Non-invasive prenatal testing (NIPT), introduced around 2011, sequences fragments of DNA from the placenta circulating in the pregnant person's blood and detects trisomy 21 with very high sensitivity, but a positive result must be confirmed by a diagnostic test such as chorionic villus sampling or amniocentesis, which carry a small risk of miscarriage.

In the United States, the American College of Obstetricians and Gynecologists recommends that all pregnant patients be offered both screening and diagnostic testing for chromosome conditions, regardless of age. Coverage of NIPT depends on the patient's insurance and state Medicaid rules, and many insurers now cover it for all pregnancies. The choice to test or not rests with the patient.

Screening raises ethical questions that genetics students should take seriously, including how information about conditions such as Down syndrome is presented, and the concern of many disability advocates that screening programs can imply that some lives are less valuable. Good practice emphasizes informed, voluntary choice and accurate, balanced information about what life with the condition can be like.

Polyploidy

Polyploidy is rare in animals but very common in plants: many crops are polyploid, including wheat (bread wheat is hexaploid, 6n = 42, combining three ancestral genomes), potato (tetraploid), strawberry (octoploid) and canola (an allotetraploid formed from two Brassica species). Polyploids often have larger cells and organs, which breeders value. Autopolyploids have extra sets from the same species; allopolyploids combine sets from two different species, as in canola and wheat. As BIOL-108 explained, polyploidy can create a new species in a single generation.

Triploids are usually sterile, because three homologues cannot pair and separate evenly in meiosis, so most gametes are unbalanced. Breeders exploit this: seedless watermelons are triploids made by crossing a tetraploid with a diploid, and commercial bananas are sterile triploids propagated from cuttings. Autotetraploids, with four copies of each chromosome, produce unusual segregation ratios. A tetraploid of genotype AAaa, if chromosomes pair at random, makes gametes AA, Aa and aa in the ratio 1 : 4 : 1, so selfing gives only 1/36 aaaa offspring instead of the 1/4 of a diploid cross.

from itertools import combinations, product
from collections import Counter
from fractions import Fraction

def tetraploid_gametes(genotype):
    """Each diploid gamete gets 2 of the 4 chromosomes, chosen at random (chromosome segregation)."""
    return Counter("".join(sorted(pair)) for pair in combinations(genotype, 2))

g = tetraploid_gametes("AAaa")
total = sum(g.values())
print("gametes of AAaa:", {k: f"{v}/{total}" for k, v in g.items()})
self_cross = Counter()
for (g1, n1), (g2, n2) in product(g.items(), g.items()):
    self_cross["".join(sorted(g1 + g2))] += n1 * n2
denom = total * total
for geno in sorted(self_cross, key=lambda s: -s.count("A")):
    print(f"  {geno}: {Fraction(self_cross[geno], denom)}")
rec = Fraction(self_cross["aaaa"], denom)
print(f"recessive phenotype in AAaa self: {rec}; dominant : recessive = {1 - rec} : {rec}")

gametes of AAaa: {'AA': '1/6', 'Aa': '4/6', 'aa': '1/6'}
  AAAA: 1/36
  AAAa: 2/9
  AAaa: 1/2
  Aaaa: 2/9
  aaaa: 1/36
recessive phenotype in AAaa self: 1/36; dominant : recessive = 35/36 : 1/36

Changes in chromosome structure

Structural changes arise when chromosomes break and the broken ends rejoin incorrectly, or when crossing over occurs between similar repeated sequences in the wrong places. There are four main types.

Inversions have a striking genetic effect: they suppress recombination. In an inversion heterozygote, homologues can pair only by forming a loop. A crossover within the loop produces chromatids that are missing some genes and duplicating others, and the resulting gametes usually fail. As a result, alleles inside an inversion are inherited as a block. Geneticists exploit this by using balancer chromosomes, which carry multiple inversions and a visible marker, to keep mutant alleles together in Drosophila stocks. In nature, inversions can keep together combinations of alleles that work well together, and they are often involved in local adaptation.

Translocations can cause cancer by placing a gene under the control of the wrong regulatory sequences or by fusing two genes. In chronic myeloid leukemia, the Philadelphia chromosome, discovered in 1960 by Peter Nowell and David Hungerford in Philadelphia, results from a translocation between chromosomes 9 and 22 that fuses the BCR and ABL1 genes, producing an overactive enzyme that drives cell division. The drug imatinib, approved in 2001, blocks that enzyme and transformed the disease from a usually fatal one to a manageable chronic condition, one of the first triumphs of targeted cancer therapy. BIOL-450 explores cancer genetics further.