13.1: Chromosomal Theory and Genetic Linkage

13.1.1: Chromosomal Theory of Inheritance

Learning Objective

List the reasons that fruit flies are excellent model organisms for genetic research

Key Points

• Homologous chromosome pairs are independent of other chromosome pairs.
• Chromosomes from each homologous pair are sorted randomly into pre-gametes.
• Parents synthesize gametes that contain only half of their chromosomes; eggs and sperm have the same number of chromosomes.
• Gametic chromosomes combine during fertilization to produce offspring with the same chromosome number as their parents.
• Eye color in fruit flies was the first X-linked trait to be discovered; thus, Morgan's experiments with fruit flies solidified the Chromosomal Theory of Inheritance.

Key Terms

wild type

the typical form of an organism, strain, gene or characteristic as it occurs in nature

hemizygous

having some single copies of genes in an otherwise diploid cell or organism

autosome

any chromosome other than sex chromosomes

Chromosomal Theory of Inheritance

The speculation that chromosomes might be the key to understanding heredity led several scientists to examine Mendel's publications and re-evaluate his model in terms of the behavior of chromosomes during mitosis and meiosis. 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 . Together, these observations led to the development of the Chromosomal Theory of Inheritance, which identified chromosomes as the genetic material responsible for Mendelian inheritance.

Sutton and Boveri

(a) Walter Sutton and (b) Theodor Boveri are credited with developing the Chromosomal Theory of Inheritance, which states that chromosomes carry the unit of heredity (genes).

The Chromosomal Theory of Inheritance was consistent with Mendel's laws and was supported by the following observations:

• 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.

Despite compelling correlations between the behavior of chromosomes during meiosis and Mendel's abstract laws, the Chromosomal Theory of Inheritance was proposed long before there was any direct evidence that traits were carried on chromosomes. Critics pointed out that individuals had far more independently segregating traits than they had chromosomes. It was only after several years of carrying out crosses with the fruit fly, Drosophila melanogaster, that Thomas Hunt Morgan provided experimental evidence to support the Chromosomal Theory of Inheritance.

In 1910, Thomas Hunt Morgan started his work with Drosophila melanogaster, a fruit fly. He chose fruit flies because they can be cultured easily, are present in large numbers, have a short generation time, and have only four pair of chromosomes that can be easily identified under the microscope. They have three pair of autosomes and a pair of sex chromosomes. At that time, he already knew that X and Y have to do with gender. He used normal flies with red eyes and mutated flies with white eyes and cross bred them. In flies, the wild type eye color is red (XW) and is dominant to white eye color (Xw) . He was able to conclude that the gene for eye color was on the X chromosome. This trait was thus determined to be X-linked and was the first X-linked trait to be identified. Males are said to be hemizygous, in that they have only one allele for any X-linked characteristic.

Eye Color in Fruit Flies

In Drosophila, the gene for eye color is located on the X chromosome. Red eye color is wild type and is dominant to white eye color.

13.1.2: Genetic Linkage and Distances

Learning Objective

Discuss how linked genes can be inherited separately

Key Points

• Alleles positioned on the same chromosome are not always inherited together because during meiosis linked genes can became unlinked.
• Frans Janssen suggested chromosomes become unlinked during homologous recombination, a process where homologous chromosomes exchange segments of DNA.
• Alfred Sturtevant hypothesized that alleles that were closer together on a gene were more likely to be inherited together rather than alleles that were farther apart and used measurements of recombination between genes to create the first genetic map.
• When genes are perfectly linked, they have a recombination frequency of 0.
• When genes are unlinked, they have a recombination frequency of 0.5, which means 50 percent of offspring are recombinants and the other 50 percent are parental types.

Key Terms

synapsis

the association of homologous maternal and paternal chromosomes during the initial part of meiosis

linkage

the property of genes of being inherited together

homologous recombination

a type of genetic recombination in which nucleotide sequences are exchanged between two similar or identical molecules of DNA

Genetic Linkage and Distances

Mendel's work suggested that traits are inherited independently of each other. Morgan identified a 1:1 ratio between a segregating trait and the X chromosome, suggesting that the random segregation of chromosomes was the physical basis of Mendel's model. This also demonstrated that linked genes disrupt Mendel's predicted outcomes. The fact that each chromosome can carry many linked genes explains how individuals can have many more traits than they have chromosomes. However, observations by researchers in Morgan's laboratory suggested that alleles positioned on the same chromosome were not always inherited together. During meiosis, linked genes somehow became unlinked.

Homologous Recombination

In 1909, Frans Janssen observed chiasmata (the point at which chromatids are in contact with each other and may exchange segments) prior to the first division of meiosis. He suggested that alleles become unlinked when 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. It is now known that the pairing and interaction between homologous chromosomes, known as synapsis, does more than simply organize the homologs for migration to separate daughter cells. When synapsed, homologous chromosomes undergo reciprocal physical exchanges of DNA at their arms in a process called homologous recombination, or more simply, "crossing over."

Genetic Maps

In 1913, Alfred Sturtevant, a student in Morgan's laboratory, created the first "chromosome map," a linear representation of gene order and relative distance on a chromosome .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 hypothesized 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, or their recombination frequency, correlated with their genetic distance from each other, relative to the locations of other genes on that chromosome . Sturtevant divided his genetic map into map units, or centimorgans (cM), in which a recombination frequency of 0.01 corresponds to 1 cM.

Inheritance Patterns of Unlinked and Linked Genes

In (a), two genes are located on different chromosomes so independent assortment occurs during meiosis. The offspring have an equal chance of being the parental type (inheriting the same combination of traits as the parents) or a nonparental type (inheriting a different combination of traits than the parents). In (b), two genes are very close together on the same chromosome so that no crossing over occurs between them. The genes are, therefore, always inherited together and all of the offspring are the parental type. In (c), two genes are far apart on the chromosome such that crossing over occurs during every meiotic event. The recombination frequency will be the same as if the genes were on separate chromosomes. (d) The actual recombination frequency of fruit fly wing length and body color that Thomas Morgan observed in 1912 was 17 percent. A crossover frequency between 0 percent and 50 percent indicates that the genes are on the same chromosome and crossover occurs some of the time.

Genetic Maps

This genetic map orders Drosophila genes on the basis of recombination frequency.

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 allowed Sturtevant to calculate distances between several genes on the same chromosome.

13.1.3: Identification of Chromosomes and Karyotypes

Learning Objective

Describe a normal human karyotype and discuss the various abnormalities that can be detected using this technique

Key Points

• A normal human karyotype contains 23 pairs of chromosomes: 22 pairs of autosomes and 1 pair of sex chromosomes, generally arranged in order from largest to smallest.
• The short arm of a chromosome is referred to as the p arm, while the long arm is designated the q arm.
• To observe a karyotype, cells are collected from a blood or tissue sample and stimulated to begin dividing; the chromosomes are arrested in metaphase, preserved in a fixative and applied to a slide where they are stained with a dye to visualize the distinct banding patterns of each chromosome pair.
• A karyotype can be used to visualize abnormalities in the chromosomes, such as an incorrect number of chromosomes, deletions, insertions, or translocations of DNA.

Key Terms

translocation

a transfer of a chromosomal segment to a new position, especially on a nonhomologous chromosome

autosome

any chromosome other than sex chromosomes

karyotype

the observed characteristics (number, type, shape etc) of the chromosomes of an individual or species

Identification of Chromosomes

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. 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, also known as an ideogram.

In a given species, chromosomes can be identified by their number, size, centromere position, and banding pattern. In a human karyotype, autosomes or "body chromosomes" (all of the non–sex chromosomes) are generally organized in approximate order of size from largest (chromosome 1) to smallest (chromosome 22). 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. The X and Y chromosomes are not autosomes and are referred to as the sex chromosomes.

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. Using this naming system, locations on chromosomes can be described consistently in the scientific literature.

Although Mendel is referred to as the "father of modern genetics," he performed his experiments with none of the tools that the geneticists of today routinely employ. One such powerful cytological technique is karyotyping, a method in which traits characterized by chromosomal abnormalities can be identified from a single cell. 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 chromosome based on its characteristic banding pattern. 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 .

A human karyotype

This karyotype is of a male human. Notice that homologous chromosomes are the same size, and have the same centromere positions and banding patterns. A human female would have an XX chromosome pair instead of the XY pair shown.

At its most basic, the karyotype may reveal genetic abnormalities in which an individual has too many or too few chromosomes per cell. 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. Geneticists can also identify large deletions or insertions of DNA. For instance, Jacobsen Syndrome, which involves distinctive facial features as well as heart and bleeding defects, is identified by a deletion on chromosome 11. Finally, the karyotype can 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. Translocations are implicated in certain cancers, including chronic myelogenous leukemia.

During Mendel's lifetime, inheritance was an abstract concept that could only be inferred by performing crosses and observing the traits expressed by offspring. By observing a karyotype, today's geneticists can actually visualize the chromosomal composition of an individual to confirm or predict genetic abnormalities in offspring, even before birth.

Attributions

• Chromosomal Theory of Inheritance
  • "Boundless." http://www.boundless.com/. Boundless Learning CC BY-SA 3.0.
  • "Robert Bear and David Rintoul, Extensions of the Laws of Inheritance. October 31, 2013." http://cnx.org/content/m47304/latest/. OpenStax CNX CC BY 3.0.
  • "autosome." http://en.wiktionary.org/wiki/autosome. Wiktionary CC BY-SA 3.0.
  • "hemizygous." http://en.wiktionary.org/wiki/hemizygous. Wiktionary CC BY-SA 3.0.
  • "wild type." http://en.wiktionary.org/wiki/wild_type. Wiktionary CC BY-SA 3.0.
  • "Structural Biochemistry/Chromosomes." http://en.wikibooks.org/wiki/Structural_Biochemistry/Chromosomes. Wikibooks CC BY-SA 3.0.
  • "OpenStax College, Biology. October 16, 2013." http://cnx.org/content/m44481/latest/?collection=col11448/latest. OpenStax CNX CC BY 3.0.
  • "OpenStax College, Chromosomal Theory and Genetic Linkage October 16, 2013." http://cnx.org/content/m44481/latest/Figure_13_01_01.jpg. OpenStax CNX CC BY 3.0.
  • "Robert Bear and David Rintoul, Extensions of the Laws of Inheritance. October 31, 2013." http://cnx.org/content/m47304/latest/. OpenStax CNX CC BY 3.0.
• Genetic Linkage and Distances
  • "Boundless." http://www.boundless.com/. Boundless Learning CC BY-SA 3.0.
  • "homologous recombination." http://en.wikipedia.org/wiki/homologous%20recombination. Wikipedia CC BY-SA 3.0.
  • "linkage." http://en.wiktionary.org/wiki/linkage. Wiktionary CC BY-SA 3.0.
  • "OpenStax College, Biology. October 16, 2013." http://cnx.org/content/m44481/latest/?collection=col11448/latest. OpenStax CNX CC BY 3.0.
  • "synapsis." http://en.wiktionary.org/wiki/synapsis. Wiktionary CC BY-SA 3.0.
  • "OpenStax College, Chromosomal Theory and Genetic Linkage October 16, 2013." http://cnx.org/content/m44481/latest/Figure_13_01_02.jpg. OpenStax CNX CC BY 3.0.
  • "OpenStax College, Chromosomal Theory and Genetic Linkage October 16, 2013." http://cnx.org/content/m44481/latest/Figure_13_01_03.png. OpenStax CNX CC BY 3.0.
• Identification of Chromosomes and Karyotypes
  • "Boundless." http://www.boundless.com/. Boundless Learning CC BY-SA 3.0.
  • "autosome." http://en.wiktionary.org/wiki/autosome. Wiktionary CC BY-SA 3.0.
  • "translocation." http://en.wiktionary.org/wiki/translocation. Wiktionary CC BY-SA 3.0.
  • "karyotype." http://en.wiktionary.org/wiki/karyotype. Wiktionary CC BY-SA 3.0.
  • "OpenStax College, Biology. October 16, 2013." http://cnx.org/content/m44483/latest/?collection=col11448/latest. OpenStax CNX CC BY 3.0.
  • "NHGRI human male karyotype." http://en.wikipedia.org/wiki/File:NHGRI_human_male_karyotype.png. Wikipedia Public domain.