Chapter 7. The Cellular Basis of Inheritance

Fertilization and meiosis alternate in sexual life cycles. What happens between these two events depends on the organism. The process of meiosis reduces the resulting gamete’s chromosome number by half. Fertilization, the joining of two haploid gametes, restores the diploid condition. There are three main categories of life cycles in multicellular organisms: diploid-dominant, in which the multicellular diploid stage is the most obvious life stage (and there is no multicellular haploid stage), as with most animals including humans; haploid-dominant, in which the multicellular haploid stage is the most obvious life stage (and there is no multicellular diploid stage), as with all fungi and some algae; and alternation of generations, in which the two stages, haploid and diploid, are apparent to one degree or another depending on the group, as with plants and some algae.

Nearly all animals employ a diploid-dominant life-cycle strategy in which the only haploid cells produced by the organism are the gametes. The gametes are produced from diploid germ cells, a special cell line that only produces gametes. Once the haploid gametes are formed, they lose the ability to divide again. There is no multicellular haploid life stage. Fertilization occurs with the fusion of two gametes, usually from different individuals, restoring the diploid state (Figure 7.2a).

Art Connection

Figure 7.2. 

(a) In animals, sexually reproducing adults form haploid gametes from diploid germ cells. (b) Fungi, such as black bread mold (Rhizopus nigricans), have haploid-dominant life cycles. (c) Plants have a life cycle that alternates between a multicellular haploid organism and a multicellular diploid organism. (credit c “fern”: modification of work by Cory Zanker; credit c “gametophyte”: modification of work by “Vlmastra”/Wikimedia Commons)

If a mutation occurs so that a fungus is no longer able to produce a minus mating type, will it still be able to reproduce?

Most fungi and algae employ a life-cycle strategy in which the multicellular “body” of the organism is haploid. During sexual reproduction, specialized haploid cells from two individuals join to form a diploid zygote. The zygote immediately undergoes meiosis to form four haploid cells called spores (Figure 7.2b).

The third life-cycle type, employed by some algae and all plants, is called alternation of generations. These species have both haploid and diploid multicellular organisms as part of their life cycle. The haploid multicellular plants are called gametophytes because they produce gametes. Meiosis is not involved in the production of gametes in this case, as the organism that produces gametes is already haploid. Fertilization between the gametes forms a diploid zygote. The zygote will undergo many rounds of mitosis and give rise to a diploid multicellular plant called a sporophyte. Specialized cells of the sporophyte will undergo meiosis and produce haploid spores. The spores will develop into the gametophytes (Figure 7.2c).

Meiosis is preceded by an interphase consisting of the G₁, S, and G₂ phases, which are nearly identical to the phases preceding mitosis. The G₁ phase is the first phase of interphase and is focused on cell growth. In the S phase, the DNA of the chromosomes is replicated. Finally, in the G₂ phase, the cell undergoes the final preparations for meiosis.

During DNA duplication of the S phase, each chromosome becomes composed of two identical copies (called sister chromatids) that are held together at the centromere until they are pulled apart during meiosis II. In an animal cell, the centrosomes that organize the microtubules of the meiotic spindle also replicate. This prepares the cell for the first meiotic phase.

Early in prophase I, the chromosomes can be seen clearly microscopically. As the nuclear envelope begins to break down, the proteins associated with homologous chromosomes bring the pair close to each other. The tight pairing of the homologous chromosomes is called synapsis. In synapsis, the genes on the chromatids of the homologous chromosomes are precisely aligned with each other. An exchange of chromosome segments between non-sister homologous chromatids occurs and is called crossing over. This process is revealed visually after the exchange as chiasmata (singular = chiasma) (Figure 7.3).

As prophase I progresses, the close association between homologous chromosomes begins to break down, and the chromosomes continue to condense, although the homologous chromosomes remain attached to each other at chiasmata. The number of chiasmata varies with the species and the length of the chromosome. At the end of prophase I, the pairs are held together only at chiasmata (Figure 7.3) and are called tetrads because the four sister chromatids of each pair of homologous chromosomes are now visible.

The crossover events are the first source of genetic variation produced by meiosis. A single crossover event between homologous non-sister chromatids leads to a reciprocal exchange of equivalent DNA between a maternal chromosome and a paternal chromosome. Now, when that sister chromatid is moved into a gamete, it will carry some DNA from one parent of the individual and some DNA from the other parent. The recombinant sister chromatid has a combination of maternal and paternal genes that did not exist before the crossover.

Figure 7.3. 

In this illustration of the effects of crossing over, the blue chromosome came from the individual’s father and the red chromosome came from the individual’s mother. Crossover occurs between non-sister chromatids of homologous chromosomes. The result is an exchange of genetic material between homologous chromosomes. The chromosomes that have a mixture of maternal and paternal sequence are called recombinant and the chromosomes that are completely paternal or maternal are called non-recombinant.

The key event in prometaphase I is the attachment of the spindle fiber microtubules to the kinetochore proteins at the centromeres. The microtubules assembled from centrosomes at opposite poles of the cell grow toward the middle of the cell. At the end of prometaphase I, each tetrad is attached to microtubules from both poles, with one homologous chromosome attached at one pole and the other homologous chromosome attached to the other pole. The homologous chromosomes are still held together at chiasmata. In addition, the nuclear membrane has broken down entirely.

During metaphase I, the homologous chromosomes are arranged in the center of the cell with the kinetochores facing opposite poles. The orientation of each pair of homologous chromosomes at the center of the cell is random.

This randomness, called independent assortment, is the physical basis for the generation of the second form of genetic variation in offspring. Consider that the homologous chromosomes of a sexually reproducing organism are originally inherited as two separate sets, one from each parent. Using humans as an example, one set of 23 chromosomes is present in the egg donated by the mother. The father provides the other set of 23 chromosomes in the sperm that fertilizes the egg. In metaphase I, these pairs line up at the midway point between the two poles of the cell. Because there is an equal chance that a microtubule fiber will encounter a maternally or paternally inherited chromosome, the arrangement of the tetrads at the metaphase plate is random. Any maternally inherited chromosome may face either pole. Any paternally inherited chromosome may also face either pole. The orientation of each tetrad is independent of the orientation of the other 22 tetrads.

In each cell that undergoes meiosis, the arrangement of the tetrads is different. The number of variations depends on the number of chromosomes making up a set. There are two possibilities for orientation (for each tetrad); thus, the possible number of alignments equals 2ⁿ where n is the number of chromosomes per set. Humans have 23 chromosome pairs, which results in over eight million (2²³) possibilities. This number does not include the variability previously created in the sister chromatids by crossover. Given these two mechanisms, it is highly unlikely that any two haploid cells resulting from meiosis will have the same genetic composition (Figure 7.4).

To summarize the genetic consequences of meiosis I: the maternal and paternal genes are recombined by crossover events occurring on each homologous pair during prophase I; in addition, the random assortment of tetrads at metaphase produces a unique combination of maternal and paternal chromosomes that will make their way into the gametes.

Figure 7.4. 

To demonstrate random, independent assortment at metaphase I, consider a cell with n = 2. In this case, there are two possible arrangements at the equatorial plane in metaphase I, as shown in the upper cell of each panel. These two possible orientations lead to the production of genetically different gametes. With more chromosomes, the number of possible arrangements increases dramatically.

In anaphase I, the spindle fibers pull the linked chromosomes apart. The sister chromatids remain tightly bound together at the centromere. It is the chiasma connections that are broken in anaphase I as the fibers attached to the fused kinetochores pull the homologous chromosomes apart (Figure 7.5).

In telophase I, the separated chromosomes arrive at opposite poles. The remainder of the typical telophase events may or may not occur depending on the species. In some organisms, the chromosomes decondense and nuclear envelopes form around the chromatids in telophase I.

Cytokinesis, the physical separation of the cytoplasmic components into two daughter cells, occurs without reformation of the nuclei in other organisms. In nearly all species, cytokinesis separates the cell contents by either a cleavage furrow (in animals and some fungi), or a cell plate that will ultimately lead to formation of cell walls that separate the two daughter cells (in plants). At each pole, there is just one member of each pair of the homologous chromosomes, so only one full set of the chromosomes is present. This is why the cells are considered haploid—there is only one chromosome set, even though there are duplicate copies of the set because each homolog still consists of two sister chromatids that are still attached to each other. However, although the sister chromatids were once duplicates of the same chromosome, they are no longer identical at this stage because of crossovers.

Concept in Action

Review the process of meiosis, observing how chromosomes align and migrate, at this site.

In meiosis II, the connected sister chromatids remaining in the haploid cells from meiosis I will be split to form four haploid cells. In some species, cells enter a brief interphase, or interkinesis, that lacks an S phase, before entering meiosis II. Chromosomes are not duplicated during interkinesis. The two cells produced in meiosis I go through the events of meiosis II in synchrony. Overall, meiosis II resembles the mitotic division of a haploid cell.

In prophase II, if the chromosomes decondensed in telophase I, they condense again. If nuclear envelopes were formed, they fragment into vesicles. The centrosomes duplicated during interkinesis move away from each other toward opposite poles, and new spindles are formed. In prometaphase II, the nuclear envelopes are completely broken down, and the spindle is fully formed. Each sister chromatid forms an individual kinetochore that attaches to microtubules from opposite poles. In metaphase II, the sister chromatids are maximally condensed and aligned at the center of the cell. In anaphase II, the sister chromatids are pulled apart by the spindle fibers and move toward opposite poles.

Figure 7.5. 

In prometaphase I, microtubules attach to the fused kinetochores of homologous chromosomes. In anaphase I, the homologous chromosomes are separated. In prometaphase II, microtubules attach to individual kinetochores of sister chromatids. In anaphase II, the sister chromatids are separated.

In telophase II, the chromosomes arrive at opposite poles and begin to decondense. Nuclear envelopes form around the chromosomes. Cytokinesis separates the two cells into four genetically unique haploid cells. At this point, the nuclei in the newly produced cells are both haploid and have only one copy of the single set of chromosomes. The cells produced are genetically unique because of the random assortment of paternal and maternal homologs and because of the recombination of maternal and paternal segments of chromosomes—with their sets of genes—that occurs during crossover.

Mitosis and meiosis, which are both forms of division of the nucleus in eukaryotic cells, share some similarities, but also exhibit distinct differences that lead to their very different outcomes. Mitosis is a single nuclear division that results in two nuclei, usually partitioned into two new cells. The nuclei resulting from a mitotic division are genetically identical to the original. They have the same number of sets of chromosomes: one in the case of haploid cells, and two in the case of diploid cells. On the other hand, meiosis is two nuclear divisions that result in four nuclei, usually partitioned into four new cells. The nuclei resulting from meiosis are never genetically identical, and they contain one chromosome set only—this is half the number of the original cell, which was diploid (Figure 7.6).

The differences in the outcomes of meiosis and mitosis occur because of differences in the behavior of the chromosomes during each process. Most of these differences in the processes occur in meiosis I, which is a very different nuclear division than mitosis. In meiosis I, the homologous chromosome pairs become associated with each other, are bound together, experience chiasmata and crossover between sister chromatids, and line up along the metaphase plate in tetrads with spindle fibers from opposite spindle poles attached to each kinetochore of a homolog in a tetrad. All of these events occur only in meiosis I, never in mitosis.

Homologous chromosomes move to opposite poles during meiosis I so the number of sets of chromosomes in each nucleus-to-be is reduced from two to one. For this reason, meiosis I is referred to as a reduction division. There is no such reduction in ploidy level in mitosis.

Meiosis II is much more analogous to a mitotic division. In this case, duplicated chromosomes (only one set of them) line up at the center of the cell with divided kinetochores attached to spindle fibers from opposite poles. During anaphase II, as in mitotic anaphase, the kinetochores divide and one sister chromatid is pulled to one pole and the other sister chromatid is pulled to the other pole. If it were not for the fact that there had been crossovers, the two products of each meiosis II division would be identical as in mitosis; instead, they are different because there has always been at least one crossover per chromosome. Meiosis II is not a reduction division because, although there are fewer copies of the genome in the resulting cells, there is still one set of chromosomes, as there was at the end of meiosis I.

Cells produced by mitosis will function in different parts of the body as a part of growth or replacing dead or damaged cells. They may even be involved in asexual reproduction in some organisms. Cells produced by meiosis in a diploid-dominant organism such as an animal will only participate in sexual reproduction.

Figure 7.6. 

Meiosis and mitosis are both preceded by one round of DNA replication; however, meiosis includes two nuclear divisions. The four daughter cells resulting from meiosis are haploid and genetically distinct. The daughter cells resulting from mitosis are diploid and identical to the parent cell.

Concept in Action

For an animation comparing mitosis and meiosis, go to this website.

The isolation and microscopic observation of chromosomes forms the basis of cytogenetics and is the primary method by which clinicians detect chromosomal abnormalities in humans. A karyotype is the number and appearance of chromosomes, including their length, banding pattern, and centromere position. To obtain a view of an individual’s karyotype, cytologists photograph the chromosomes and then cut and paste each chromosome into a chart, or karyogram (Figure 7.7).

Figure 7.7. 

This karyogram shows the chromosomes of a female human immune cell during mitosis. (credit: Andreas Bolzer, et al)

Nondisjunctions, Duplications, and Deletions

Of all the chromosomal disorders, abnormalities in chromosome number are the most easily identifiable from a karyogram. Disorders of chromosome number include the duplication or loss of entire chromosomes, as well as changes in the number of complete sets of chromosomes. They are caused by nondisjunction, which occurs when pairs of homologous chromosomes or sister chromatids fail to separate during meiosis. The risk of nondisjunction increases with the age of the parents.

Nondisjunction can occur during either meiosis I or II, with different results (Figure 7.8). If homologous chromosomes fail to separate during meiosis I, the result is two gametes that lack that chromosome and two gametes with two copies of the chromosome. If sister chromatids fail to separate during meiosis II, the result is one gamete that lacks that chromosome, two normal gametes with one copy of the chromosome, and one gamete with two copies of the chromosome.

Figure 7.8. 

Following meiosis, each gamete has one copy of each chromosome. Nondisjunction occurs when homologous chromosomes (meiosis I) or sister chromatids (meiosis II) fail to separate during meiosis.

An individual with the appropriate number of chromosomes for their species is called euploid; in humans, euploidy corresponds to 22 pairs of autosomes and one pair of sex chromosomes. An individual with an error in chromosome number is described as aneuploid, a term that includes monosomy (loss of one chromosome) or trisomy (gain of an extraneous chromosome). Monosomic human zygotes missing any one copy of an autosome invariably fail to develop to birth because they have only one copy of essential genes. Most autosomal trisomies also fail to develop to birth; however, duplications of some of the smaller chromosomes (13, 15, 18, 21, or 22) can result in offspring that survive for several weeks to many years. Trisomic individuals suffer from a different type of genetic imbalance: an excess in gene dose. Cell functions are calibrated to the amount of gene product produced by two copies (doses) of each gene; adding a third copy (dose) disrupts this balance. The most common trisomy is that of chromosome 21, which leads to Down syndrome. Individuals with this inherited disorder have characteristic physical features and developmental delays in growth and cognition. The incidence of Down syndrome is correlated with maternal age, such that older women are more likely to give birth to children with Down syndrome (Figure 7.9).

Figure 7.9. 

The incidence of having a fetus with trisomy 21 increases dramatically with maternal age.

Concept in Action

Visualize the addition of a chromosome that leads to Down syndrome in this video simulation.

Humans display dramatic deleterious effects with autosomal trisomies and monosomies. Therefore, it may seem counterintuitive that human females and males can function normally, despite carrying different numbers of the X chromosome. In part, this occurs because of a process called X inactivation. Early in development, when female mammalian embryos consist of just a few thousand cells, one X chromosome in each cell inactivates by condensing into a structure called a Barr body. The genes on the inactive X chromosome are not expressed. The particular X chromosome (maternally or paternally derived) that is inactivated in each cell is random, but once the inactivation occurs, all cells descended from that cell will have the same inactive X chromosome. By this process, females compensate for their double genetic dose of X chromosome.

In so-called “tortoiseshell” cats, X inactivation is observed as coat-color variegation (Figure 7.10). Females heterozygous for an X-linked coat color gene will express one of two different coat colors over different regions of their body, corresponding to whichever X chromosome is inactivated in the embryonic cell progenitor of that region. When you see a tortoiseshell cat, you will know that it has to be a female.

Figure 7.10. 

Embryonic inactivation of one of two different X chromosomes encoding different coat colors gives rise to the tortoiseshell phenotype in cats. (credit: Michael Bodega)

In an individual carrying an abnormal number of X chromosomes, cellular mechanisms will inactivate all but one X in each of her cells. As a result, X-chromosomal abnormalities are typically associated with mild mental and physical defects, as well as sterility. If the X chromosome is absent altogether, the individual will not develop.

Several errors in sex chromosome number have been characterized. Individuals with three X chromosomes, called triplo-X, appear female but express developmental delays and reduced fertility. The XXY chromosome complement, corresponding to one type of Klinefelter syndrome, corresponds to male individuals with small testes, enlarged breasts, and reduced body hair. The extra X chromosome undergoes inactivation to compensate for the excess genetic dosage. Turner syndrome, characterized as an X0 chromosome complement (i.e., only a single sex chromosome), corresponds to a female individual with short stature, webbed skin in the neck region, hearing and cardiac impairments, and sterility.

An individual with more than the correct number of chromosome sets (two for diploid species) is called polyploid. For instance, fertilization of an abnormal diploid egg with a normal haploid sperm would yield a triploid zygote. Polyploid animals are extremely rare, with only a few examples among the flatworms, crustaceans, amphibians, fish, and lizards. Triploid animals are sterile because meiosis cannot proceed normally with an odd number of chromosome sets. In contrast, polyploidy is very common in the plant kingdom, and polyploid plants tend to be larger and more robust than euploids of their species.

Cytologists have characterized numerous structural rearrangements in chromosomes, including partial duplications, deletions, inversions, and translocations. Duplications and deletions often produce offspring that survive but exhibit physical and mental abnormalities. Cri-du-chat (from the French for “cry of the cat”) is a syndrome associated with nervous system abnormalities and identifiable physical features that results from a deletion of most of the small arm of chromosome 5 (Figure 7.11). Infants with this genotype emit a characteristic high-pitched cry upon which the disorder’s name is based.

Figure 7.11. 

This individual with cri-du-chat syndrome is shown at various ages: (A) age two, (B) age four, (C) age nine, and (D) age 12. (credit: Paola Cerruti Mainardi)

Chromosome inversions and translocations can be identified by observing cells during meiosis because homologous chromosomes with a rearrangement in one of the pair must contort to maintain appropriate gene alignment and pair effectively during prophase I.

A chromosome inversion is the detachment, 180° rotation, and reinsertion of part of a chromosome (Figure 7.12). Unless they disrupt a gene sequence, inversions only change the orientation of genes and are likely to have more mild effects than aneuploid errors.

A translocation occurs when a segment of a chromosome dissociates and reattaches to a different, nonhomologous chromosome. Translocations can be benign or have devastating effects, depending on how the positions of genes are altered with respect to regulatory sequences. Notably, specific translocations have been associated with several cancers and with schizophrenia. Reciprocal translocations result from the exchange of chromosome segments between two nonhomologous chromosomes such that there is no gain or loss of genetic information (Figure 7.12).

Figure 7.12. 

An (a) inversion occurs when a chromosome segment breaks from the chromosome, reverses its orientation, and then reattaches in the original position. A (b) reciprocal translocation occurs between two nonhomologous chromosomes and does not cause any genetic information to be lost or duplicated. (credit: modification of work by National Human Genome Research Institute (USA)