13: Modern Understandings of Inheritance

Question 1

What is a centimorgan (cM)?

Answer 1

The relative distance that corresponds to a recombination frequency of 0.01. AKA map unit.

Question 2

What is the Chromosomal Theory of Inheritance?

Answer 2

Theory proposing that chromosomes are the vehicles of genes and that their behavior during meiosis is the physical basis of the inheritance patterns that Mendel observed.

Question 3

What is homologous recombination?

Answer 3

The process by which homologous chromosomes undergo reciprocal physical exchanges at their arms, also known as crossing over.

Question 4

What is a nonparental (recombinant) type?

Answer 4

Progeny resulting from homologous recombination that exhibits a different allele combination compared with its parents.

Question 5

What are parental types?

Answer 5

Progeny that exhibits the same allelic combination as its parents.

Question 6

What is recombination frequency?

Answer 6

The average number of crossovers between two alleles; observed as the number of nonparental types in a population of progeny.

Question 7

Which experiments led to the development of the Chromosomal Theory of Inheritance?

Answer 7

In 1902, Theodor Boveri observed that proper embryonic development of sea urchins does not occur unless chromosomes are present. That same year, Walter Sutton observed the separation of chromosomes into daughter cells during meiosis.

Question 8

Which observations support the Chromosomal Theory of Inheritance?

Answer 8

• During meiosis, homologous chromosome pairs migrate as discrete structures that are independent of other chromosome pairs.
• The sorting of chromosomes from each homologous pair into pre-gametes appears to be random.
• Each parent synthesizes gametes that contain only half of their chromosomal complement.
• Even though male and female gametes (sperm and egg) differ in size and morphology, they have the same number of chromosomes, suggesting equal genetic contributions from each parent.
• The gametic chromosomes combine during fertilization to produce offspring with the same chromosome number as their parents.

Question 9

How was genetic recombination discovered?

Answer 9

In 1909, Frans Janssen observed chiasmata prior to the first division of meiosis. He suggested that alleles become unlinked and chromosomes physically exchange segments. As chromosomes condensed and paired with their homologs, they appeared to interact at distinct points. Janssen suggested that these points corresponded to regions in which chromosome segments were exchanged.

Question 10

Who created the first genetic map?

Answer 10

In 1913, Alfred Sturtevant, a student in Morgan’s laboratory, gathered results from researchers in the laboratory, and took them home one night to mull them over. By the next morning, he had created the first “chromosome map,” a linear representation of gene order and relative distance on a chromosome.

Question 11

What were the assumptions that led to the creation of the first genetic map?

Answer 11

To construct a chromosome map, Sturtevant assumed that genes were ordered serially on threadlike chromosomes. He also assumed that the incidence of recombination between two homologous chromosomes could occur with equal likelihood anywhere along the length of the chromosome. Operating under these assumptions, Sturtevant postulated that alleles that were far apart on a chromosome were more likely to dissociate during meiosis simply because there was a larger region over which recombination could occur. Conversely, alleles that were close to each other on the chromosome were likely to be inherited together. The average number of crossovers between two alleles—that is, their recombination frequency—correlated with their genetic distance from each other, relative to the locations of other genes on that chromosome.

Question 12

How was linkage determined from recombination frequency?

Answer 12

By representing alleles in a linear map, Sturtevant suggested that genes can range from being perfectly linked (recombination frequency = 0) to being perfectly unlinked (recombination frequency = 0.5) when genes are on different chromosomes or genes are separated very far apart on the same chromosome. Perfectly unlinked genes correspond to the frequencies predicted by Mendel to assort independently in a dihybrid cross. A recombination frequency of 0.5 indicates that 50 percent of offspring are recombinants and the other 50 percent are parental types. That is, every type of allele combination is represented with equal frequency. This representation allowed Sturtevant to additively calculate distances between several genes on the same chromosome. However, as the genetic distances approached 0.50, his predictions became less accurate because it was not clear whether the genes were very far apart on the same chromosome or on different chromosomes.

Question 13

How was homologous recombination experimentally demonstrated?

Answer 13

In 1931, Barbara McClintock and Harriet Creighton demonstrated the crossover of homologous chromosomes in corn plants. Weeks later, homologous recombination in Drosophila was demonstrated microscopically by Curt Stern. Stern observed several X-linked phenotypes that were associated with a structurally unusual and dissimilar X chromosome pair in which one X was missing a small terminal segment, and the other X was fused to a piece of the Y chromosome. By crossing flies, observing their offspring, and then visualizing the offspring’s chromosomes, Stern demonstrated that every time the offspring allele combination deviated from either of the parental combinations, there was a corresponding exchange of an X chromosome segment. Using mutant flies with structurally distinct X chromosomes was the key to observing the products of recombination because DNA sequencing and other molecular tools were not yet available.

Question 14

What might have been the impact of gene linkage on Mendel’s discoveries?

Answer 14

Homologous recombination is a common genetic process, yet Mendel never observed it. Had he investigated both linked and unlinked genes, it would have been much more difficult for him to create a unified model of his data on the basis of probabilistic calculations. Researchers who have since mapped the seven traits investigated by Mendel onto the seven chromosomes of the pea plant genome have confirmed that all of the genes he examined are either on separate chromosomes or are sufficiently far apart as to be statistically unlinked. Some have suggested that Mendel was enormously lucky to select only unlinked genes, whereas others question whether Mendel discarded any data suggesting linkage. In any case, Mendel consistently observed independent assortment because he examined genes that were effectively unlinked.

Question 15

What does it mean to be aneuploid?

Answer 15

An individual with an error in chromosome number; includes deletions and duplications of chromosome segments.

Question 16

What is an autosome?

Answer 16

Any of the non-sex chromosomes.

Question 17

What is chromosome inversion?

Answer 17

Detachment, 180° rotation, and reinsertion of a chromosome arm.

Question 18

What does it mean to be euploid?

Answer 18

An individual with the appropriate number of chromosomes for their species.

Question 19

What is a karyogram?

Answer 19

A photographic image of a karyotype. AKA ideogram.

Question 20

What is a karyotype?

Answer 20

The number and appearance of an individual’s chromosomes; includes the size, banding patterns, and centromere position.

Question 21

What is monosomy?

Answer 21

An otherwise diploid genotype in which one chromosome is missing.

Question 22

What is nondisjunction?

Answer 22

The failure of synapsed homologs to completely separate and migrate to separate poles during the first cell division of meiosis.

Question 23

What does it mean to be paracentric?

Answer 23

An inversion that occurs outside of the centromere.

Question 24

What does it mean to be pericentric?

Answer 24

An inversion that involves the centromere.

Question 25

What does it mean to be polyploid?

Answer 25

An individual with more than the correct number of chromosome sets.

Question 26

What is translocation?

Answer 26

The process by which one segment of a chromosome dissociates and reattaches to a different, nonhomologous chromosome.

Question 27

What is trisomy?

Answer 27

An otherwise diploid genotype in which one entire chromosome is duplicated.

Question 28

What is X inactivation?

Answer 28

Condensation of X chromosomes into Barr bodies during embryonic development in females to compensate for the double genetic dose.

Question 29

How are chromosomes ordered in a karyotype?

Answer 29

In a human karyotype, autosomes are generally organized in approximate order of size from largest (chromosome 1) to smallest (chromosome 22). The X and Y chromosomes are not autosomes. However, chromosome 21 is actually shorter than chromosome 22. This was discovered after the naming of Down syndrome as trisomy 21, reflecting how this disease results from possessing one extra chromosome 21 (three total). Not wanting to change the name of this important disease, chromosome 21 retained its numbering, despite describing the shortest set of chromosomes.

Question 30

How are the arms of chromosomes denoted in a karyotype?

Answer 30

The chromosome arms projecting from either end of the centromere may be designated as short or long, depending on their relative lengths. The short arm is abbreviated p (for “petite”), whereas the long arm is abbreviated q (because it follows “p” alphabetically). Each arm is further subdivided and denoted by a number.

Question 31

How is a karyotype performed?

Answer 31

To observe an individual’s karyotype, a person’s cells (like white blood cells) are first collected from a blood sample or other tissue. In the laboratory, the isolated cells are stimulated to begin actively dividing. A chemical called colchicine is then applied to cells to arrest condensed chromosomes in metaphase. Cells are then made to swell using a hypotonic solution so the chromosomes spread apart. Finally, the sample is preserved in a fixative and applied to a slide.

The geneticist then stains chromosomes with one of several dyes to better visualize the distinct and reproducible banding patterns of each chromosome pair. Following staining, the chromosomes are viewed using bright-field microscopy. A common stain choice is the Giemsa stain. Giemsa staining results in approximately 400–800 bands (of tightly coiled DNA and condensed proteins) arranged along all of the 23 chromosome pairs; an experienced geneticist can identify each band. In addition to the banding patterns, chromosomes are further identified on the basis of size and centromere location. To obtain the classic depiction of the karyotype in which homologous pairs of chromosomes are aligned in numerical order from longest to shortest, the geneticist obtains a digital image, identifies each chromosome, and manually arranges the chromosomes into this pattern.

Question 32

What are some genetic abnormalities that karyotypes can be used to identify?

Answer 32

A karyogram may reveal genetic abnormalities in which an individual has too many or too few chromosomes per cell. Geneticists can also identify large deletions or insertions of DNA. The karyotype can also pinpoint translocations, which occur when a segment of genetic material breaks from one chromosome and reattaches to another chromosome or to a different part of the same chromosome.

Question 33

What are some examples of disorders caused by too many or too few chromosomes?

Answer 33

Examples of this are Down Syndrome, which is identified by a third copy of chromosome 21, and Turner Syndrome, which is characterized by the presence of only one X chromosome in women instead of the normal two.

Question 34

What is an example of a disorder caused by deletions of DNA from a chromosome?

Answer 34

Jacobsen Syndrome—which involves distinctive facial features as well as heart and bleeding defects—is identified by a deletion on chromosome 11.

Question 35

What is an example of a disorder caused by translocations?

Answer 35

Translocations are implicated in certain cancers, including chronic myelogenous leukemia.

Question 36

What is the cause of aneuploidy?

Answer 36

They are caused by nondisjunction, which occurs when pairs of homologous chromosomes or sister chromatids fail to separate during meiosis. Misaligned or incomplete synapsis, or a dysfunction of the spindle apparatus that facilitates chromosome migration, can cause nondisjunction. The risk of nondisjunction occurring increases with the age of the parents.

Question 37

When does nondisjunction occur?

Answer 37

Nondisjunction can occur during either meiosis I or II, with differing results. If homologous chromosomes fail to separate during meiosis I, the result is two gametes that lack that particular 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.

Question 38

What is the impact of monosomy on human development?

Answer 38

Monosomic human zygotes missing any one copy of an autosome invariably fail to develop to birth because they lack essential genes. This underscores the importance of “gene dosage” in humans.

Question 39

What is the impact of trisomy on human development?

Answer 39

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. Individuals with an extra chromosome may synthesize an abundance of the gene products encoded by that chromosome. This extra dose (150 percent) of specific genes can lead to a number of functional challenges and often precludes development.

Question 40

What is the impact of trisomy of chromosome 21?

Answer 40

The most common trisomy among viable births is that of chromosome 21, which corresponds to Down Syndrome. Individuals with this inherited disorder are characterized by short stature and stunted digits, facial distinctions that include a broad skull and large tongue, and significant developmental delays. The incidence of Down syndrome is correlated with maternal age; older women are more likely to become pregnant with fetuses carrying the trisomy 21 genotype.

Question 41

How common is polyploidy?

Answer 41

Polyploid animals are extremely rare, with only a few examples among the flatworms, crustaceans, amphibians, fish, and lizards. Polyploid animals are sterile because meiosis cannot proceed normally and instead produces mostly aneuploid daughter cells that cannot yield viable zygotes. Rarely, polyploid animals can reproduce asexually by haplodiploidy, in which an unfertilized egg divides mitotically to produce offspring. 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.

Question 42

Why are variations in the number of sex chromosomes associated with relatively mild effects?

Answer 42

Rather than a gain or loss of autosomes, variations in the number of sex chromosomes are associated with relatively mild effects. In part, this occurs because of a molecular process called X inactivation. Early in development, when female mammalian embryos consist of just a few thousand cells (relative to trillions in the newborn), one X chromosome in each cell inactivates by tightly condensing into a quiescent (dormant) structure called a Barr body. The chance that an X chromosome (maternally or paternally derived) is inactivated in each cell is random, but once the inactivation occurs, all cells derived from that one will have the same inactive X chromosome or Barr body. By this process, females compensate for their double genetic dose of X chromosome.

Question 43

What is an example of X-inactivation occurring in cats?

Answer 43

In so-called “tortoiseshell” cats, embryonic X inactivation is observed as color variegation. Females that are 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.

Question 44

What is the impact of X-inactivation in humans?

Answer 44

An individual carrying an abnormal number of X chromosomes will inactivate all but one X chromosome in each of her cells. However, even inactivated X chromosomes continue to express a few genes, and X chromosomes must reactivate for the proper maturation of female ovaries. 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 in utero.

Question 45

What is the impact on females with three X chromosomes?

Answer 45

Individuals with three X chromosomes, called triplo-X, are phenotypically female but express developmental delays and reduced fertility.

Question 46

What is the impact on males with multiple X chromosomes?

Answer 46

The XXY genotype, corresponding to one type of Klinefelter syndrome, corresponds to phenotypically male individuals with small testes, enlarged breasts, and reduced body hair. More complex types of Klinefelter syndrome exist in which the individual has as many as five X chromosomes. In all types, every X chromosome except one undergoes inactivation to compensate for the excess genetic dosage. This can be seen as several Barr bodies in each cell nucleus.

Question 47

What is the impact on females with only a single X chromosome?

Answer 47

Turner syndrome, characterized as an X0 genotype (i.e., only a single sex chromosome), corresponds to a phenotypically female individual with short stature, webbed skin in the neck region, hearing and cardiac impairments, and sterility.

Question 48

What is the impact on individuals of chromosomal deletions and duplications?

Answer 48

Duplications and deletions often produce offspring that survive but exhibit physical and mental abnormalities. Duplicated chromosomal segments may fuse to existing chromosomes or may be free in the nucleus.

Question 49

What is an example of a disorder caused by chromosomal deletions?

Answer 49

Cri-du-chat (from the French for “cry of the cat”) is a syndrome associated with nervous system abnormalities and identifiable physical features that result from a deletion of most of 5p (the small arm of chromosome 5). Infants with this genotype emit a characteristic high-pitched cry on which the disorder’s name is based.

Question 50

What is the cause of chromosomal structural rearrangements?

Answer 50

Cytologists have characterized numerous structural rearrangements in chromosomes, but chromosome inversions and translocations are the most common. Both are identified during meiosis by the adaptive pairing of rearranged chromosomes with their former homologs to maintain appropriate gene alignment. If the genes carried on two homologs are not oriented correctly, a recombination event could result in the loss of genes from one chromosome and the gain of genes on the other. This would produce aneuploid gametes.

Question 51

What is the impact of chromosome inversions?

Answer 51

Inversions may occur in nature as a result of mechanical shear, or from the action of transposable elements (special DNA sequences capable of facilitating the rearrangement of chromosome segments with the help of enzymes that cut and paste DNA sequences). Unless they disrupt a gene sequence, inversions only change the orientation of genes and are likely to have more mild effects than aneuploid errors. However, altered gene orientation can result in functional changes because regulators of gene expression could be moved out of position with respect to their targets, causing aberrant levels of gene products.

Question 52

What happens if a pericentric inversion is asymmetric about the centromere?

Answer 52

A pericentric inversion that is asymmetric about the centromere can change the relative lengths of the chromosome arms, making these inversions easily identifiable.

Question 53

What happens when an inversion occurs in only one homologous chromosome?

Answer 53

When one homologous chromosome undergoes an inversion but the other does not, the individual is described as an inversion heterozygote. To maintain point-for-point synapsis during meiosis, one homolog must form a loop, and the other homolog must mold around it. Although this topology can ensure that the genes are correctly aligned, it also forces the homologs to stretch and can be associated with regions of imprecise synapsis.

Question 54

How might structural rearrangement of chromosomes contributed to the evolution of humans?

Answer 54

In rare instances, structural rearrangements of chromosomes can result in the evolution of a new species. A pericentric inversion in chromosome 18 appears to have contributed to the evolution of humans. This inversion is not present in our closest genetic relatives, the chimpanzees. Humans and chimpanzees differ cytogenetically by pericentric inversions on several chromosomes and by the fusion of two separate chromosomes in chimpanzees that correspond to chromosome two in humans.

Question 55

When did pericentric chromosome 18 inversion occur in early humans?

Answer 55

The pericentric chromosome 18 inversion is believed to have occurred in early humans following their divergence from a common ancestor with chimpanzees approximately five million years ago. Researchers characterizing this inversion have suggested that approximately 19,000 nucleotide bases were duplicated on 18p, and the duplicated region inverted and reinserted on chromosome 18 of an ancestral human.

Question 56

Which genes are important in the pericentric chromosome 18 inversion of humans?

Answer 56

A comparison of human and chimpanzee genes in the region of this inversion indicates that two genes—ROCK1 and USP14—that are adjacent on chimpanzee chromosome 17 (which corresponds to human chromosome 18) are more distantly positioned on human chromosome 18. This suggests that one of the inversion breakpoints occurred between these two genes. Interestingly, humans and chimpanzees express USP14 at distinct levels in specific cell types, including cortical cells and fibroblasts. Perhaps the chromosome 18 inversion in an ancestral human repositioned specific genes and reset their expression levels in a useful way. Because both ROCK1 and USP14 encode cellular enzymes, a change in their expression could alter cellular function. It is not known how this inversion contributed to hominid evolution, but it appears to be a significant factor in the divergence of humans from other primates.

Question 57

What is the impact of translocations?

Answer 57

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.