Linked and Sex-Linked Genes
The dihybrid cross we previously did assumed the genes were on different pairs of chromosomes. Now, we want to look at an example where the genes involved are on the same chromosome. One such example is the flower color and pollen shape experiment done by Bateson and Punnett. In the plants that they studied, the genes for pollen shape and flower color are located on the same chromosome (pair) as each other, thus are inherited together.
Linked Genes If the parents are PPLL × ppll, the first parent will only make gametes with PL and the second with pl, which doesn’t seem too different so far. From these parents, the F1 generation would all be PpLl. However, when calculating what the F2 generation will be, since the genes are located on the same pair of chromosomes, then theoretically, the only possible gametes are PL and pl (not Pl or pL). So
The phenotype ratio for this cross is 3:1, not 9:3:3:1 as would be expected for a “normal” dihybrid cross. Because these genes are on the same chromosome pair, they are called linked genes. Interestingly, Bateson and Punnett’s results showed just a few, unexpected ppL- and P-ll offspring, more than would be predicted by linked genes, but far less than would be predicted by unlinked genes in a “regular” dihybrid cross. This is due to the fact that occasionally, during synapsis in meiosis I, while the homologous chromosomes are paired up, sister chromatids from the homologous chromosomes exchange equal segments. This is called crossing over. In the flower example, a few of the plants could exhibit crossing over during meiosis I, producing a few pL and Pl gametes, which would account for the small number of ppL- and P-ll offspring. T. H. Morgan and his grad students, who studied fruitflies, found that the farther apart two genes are on a chromosome, the more likely there is to be crossing over between those two genes. They found that for any given two genes on the same chromosome as each other, the amount of crossing over that occurs is a fairly constant quantity that can be measured. From their crossing over data, Morgan et al. were able to arrange fruit fly genes in the order in which they occur on the fruit fly chromosomes. Interestingly, if two genes are very far apart on the same chromosome pair, there is so much crossing over that the results obtained look like a regular dihybrid cross between unlinked genes.
Linked Genes and Crossing Over in Fruit Flies
Normal fruit flies
have grayish-yellow bodies, red eyes, and wings that are long-enough to be
able to fly. As Morgan and his students were breeding fruit flies, they
found mutant flies with black bodies, some with stumpy, vestigial wings,
and some with a brighter, orangish-red eye color that they called “cinnabar,”
and by breeding flies, they were able to determine that all three of these
mutations were recessive and were on the autosomes.
Fruit fly researchers use a different type of symbolism to represent their genetic crosses. Those researchers use a plus sign (+) to indicate anything that is the “wild” type and a letter or two to represent a mutant allele (capital for dominant, lower case for recessive). Thus a fruit fly with a homozygous grayish-yellow body would be labeled as “++” while a black-bodied fly would be “bb” and a heterozygous fly would be “+b”. The symbol for vestigial wings is “vg” and the symbol for cinnabar eyes is ”cn”.
Through breeding, Morgan and his students were able to obtain flies that had both a black body and vestigial wings (bbvgvg). They bred some of those flies with wild type flies to obtain flies that were heterozygous for both traits (+b+vg). Then they did a testcross by crossing the +b+vg heterozygous flies with bbvgvg flies, and counted a total of 2300 offspring.
If the genes were on different chromosomes, the Punnett square for this cross would look like this:
|(206 + 185)||× 100 = 17%|
There is yet another, unrelated, special case that means something totally different, yet has a similar-sounding name (just to confuse freshman biology students?). This is sex-linked genes, genes located on one of the sex chromosomes (X or Y) but not the other. Since, typically the X chromosome is longer, it bears a lot of genes not found on the Y chromosome, thus most sex-linked genes are X-linked genes. One example of a sex-linked gene is fruit fly eye color (one of the main genes for that — there are several genes involved). An X chromosome carrying a normal, dominant, red-eyed allele would be symbolized by a plain X, while the recessive, mutant, white-eyed allele would be symbolized by X' or Xw. A fly with genotype XX' would normally be a female with red eyes, yet would be a carrier for the white-eyed allele. Because a male typically only has one X chromosome, he would normally be either XY and have normal, red eyes, or X'Y and have white eyes. The only way a female with two X chromosomes could have white eyes is if she would get an X' allele from both parents making her X'X' genotype. The cross between a female carrier and a red-eyed male would look like this:
Notice that while there is a “typical” ratio of ľ red-eyed to Ľ white-eyed, all of the white-eyed flies are males.
Typically, X-linked traits show up more in males than females because typical XY males only have one X chromosome, so if they get the allele on their X chromosome, they show the trait. If a typical XX female is a carrier, 50% of her sons will get that X chromosome and show the trait. In order for an XX female to exhibit one of these X-linked traits, most of which are recessive mutations, she would have to have two copies of the allele (X'X'), which would mean that her mother would have to be a carrier and her father have the trait so she could get one allele from each of them.
In humans, two well-known X-linked traits are hemophilia and red-green colorblindness. Hemophilia is the failure (lack of genetic code) to produce certain substance needed for proper blood-clotting, so a hemophiliac’s blood doesn’t clot, and (s)he could bleed to death from an injury that a normal person might not even notice. One of the most famous genetic cases involving hemophilia goes back to Queen Victoria. While both of her parents were perfectly normal, it is usually assumed that a chance mutation in either the egg or sperm that came together to make her, caused her to be a carrier for the hemophilia allele (XX') [see the box, below, for an alternative hypothesis that some people have suggested]. When she grew up, she married Prince Albert, who was normal XY, so the Punnett square for their marriage would look like the one just drawn. The Punnett square would predict that ˝ of their sons (Ľ of their children) would be hemophiliacs and ˝ of their daughters (Ľ of their children) would be carriers. Their children married other royalty, and spread the gene throughout the royal families of Europe.
Genetics Plays a Role in History
daughter, Alice, married a German prince, Louis, and converted to Lutheranism.
Their daughter, Queen Victoria’s granddaughter, Alexandra was, thus, a German
princess, grew up in Germany, and was raised in the Lutheran church.
Alexandra, married Tsar Nicholas, the last tsar of Russia, and they had four
daughters: Olga, Tatiana, Marie, and Anastasia. Many people in Russia
didn’t like Tsarina Alexandra because she was German, not Russian, and
Lutheran, not Russian Orthodox. Her mannerisms, speech, and dress were not
what many people in Russia thought of as appropriate for the Tsar’s wife.
Also, in Russia at that time, only a male could be tsar, so unless Alexandra
and Nicholas had a son, the leadership would pass to another of Nicholas’
relatives when he died. Finally, however, they had a son who they named
Alexei. Unfortunately, however, they soon discovered that he had inherited
the hemophilia allele from Alexandra, from Alice, and from Queen Victoria.
Realizing that chances were very slim that Alexei would survive to adulthood,
Tsar Nicholas and his family became very withdrawn to try to keep that a
secret (Alexandra was not very outgoing, anyway, which the people didn’t
like). However, at that time, there was much social unrest in Russia, and
the general public mistook the royal family’s withdrawl for aloofness and as
a sign that they didn’t care about the poor living conditions of their people.
Thus, Alexei’s hemophilia was probably a major contributing factor in the
Russian revolution. On several occasions, Alexei had severe internal
bleeding, and a rather disreputable man named Rasputin was somehow able to
stop the bleeding. Because of his inexplicable ability to help Alexei,
Rasputin became part of the “inner circle” and close confidant of the royal
family, which also angered many people who did not trust him.
Thus, when the Russian Revolution began, Rasputin was among the first to be executed. Eventually, Tsar Nicholas and his family were put under house arrest in Siberia. On 18 June 1918, Anastasia, the youngest of the daughters, turned 17 while the family was still under house arrest, and about a month later, just after midnight on 16 July, the royal family and several of their servants were all ordered down into the basement of the house, and the soldiers who had been guarding them shot and killed them all. Then, their remains were taken out of town, burned in a bonfire, then buried, together, in an unmarked grave. For years, no one knew where that grave was until, when Communist rule ended, records became available. In 1991, what was thought to, perhaps, be that grave was found, the bones were carefully removed, and as much as possible, the skeletons were reconstructed. Through the use of modern DNA technology, DNA samples from the bones were compared to DNA from the Tsar’s brother’s body (buried in a crypt in a church in St. Petersburg) and to DNA from someone in the English royal family. On that basis, one adult male skeleton was identified as the Tsar, several young adult female skeletons were identified as several of the daughters, and the DNA of several of the other skeletons didn’t match, showing that they were unrelated, family servants. The skeletons of Alexei and one of the four daughters were not with the rest, and are still unaccounted for (I’ve subsequently read that another grave was found nearby,and it is thought that probably contains their bones). After the bones were studied and identified, a few years ago, the remains of the last Tsar of Russia and his family were given a proper funeral and burial.
In 1919, a young woman jumped off a bridge in Berlin, Germany and was rescued and hospitalized. While in the hospital, on one occasion she showed a magazine article with a photo of the Russian royal family to a nurse, pointing out to the nurse how much she thought she looked like Anastasia. After that, she claimed to be Anastasia and claimed to have escaped and survived. She later moved to the U. S. and went by the name of Anna Anderson. The rest of her life, she stuck to her story that she was Anastasia, but people were dubious and tried everything they could think of (including things like comparing pictures of ear lobes) to figure out whether she was Anastasia, or not. When she died and was cremated in 1984, no one still knew if she was really Anastasia or not. At some point before her death, she had had surgery, and the hospital had kept the removed tissue preserved in formaldehyde. Again in the 1990s, with the advent of modern DNA technology, scientists were also able to test DNA samples from her preserved tissue and compare those to the other DNA samples, with the result that there were no similarities – she was not related.
Another possible use for DNA technology has been suggested. The big question in all of this is, “From where did Victoria get the hemophilia allele?” Neither her mother, Victoria, nor her father, King Edward showed any signs of having that allele. The “standard” explanation which, for many years, has been offered to freshman biology students is that there was a chance, random mutation in that allele on one of Queen Victoria’s X chromosomes. More recently, however, I have heard suggestions (from people that weren’t around back then, and so don’t really know the story) that, at that time, if the royal couple was having trouble conceiving a child, it would not have been out of the question to quietly, unobtrusively “loan” the Queen out. Certain people have raised the suggestion that maybe King Edward is not Victoria’s biological father. It has been suggested that perhaps there was not a chance mutation in one of Queen Victoria’s X chromosomes, but that, perhaps, that was inherited from another man. Since the bodies of deceased members of the royal family are in crypts in Westminster Abbey, it would be fairly easy to lift the lids on a couple of crypts to get DNA samples for comparison, but needless to say, the British royal family probably isn’t very enthused about that idea.
Again, colorblindness and hemophilia, while rare overall, are more common in XY males, because they only have one X chromosome. For an XX woman to be colorblind, for example, her mother would have to be a carrier for the trait and her father would have to be colorblind. If by some chance, considering the overall rareness of the allele, two such people met and married, 50% of their daughters would be colorblind.
Female Buccal Cells: Barr bodies are small black dots
noticeable in cells/nuclei at 9:00 and 2:30 We have previously mentioned that it’s very important to have exactly two copies of each chromosome (one from the mother and one from the father), and more or less chromosomes would be an abnormal number that can cause problems. How is it, then, that we can get by with females being XX and having two copies of all of the genes on the X chromosome, while males, being XY, only have one copy of most of those genes because there are no corresponding places on the Y chromosome? Dr. Barr noticed a dark spot in the nucleus of each cell in the body of female mammals. Mary Lyon figured out what this was and what was going on here. In a female mammal, during embryonic development, one X at random is turned off in each of her cells and condenses to form the dark spot. Mary Lyon called these inactivated X-chromosomes “Barr bodies” in honor of Dr. Barr. She also figured out that as those embryonic cells divide, all daughter cells of each of those cells will have the same X turned off.
This is illustrated by calico cats. Coat color in cats is an X-linked gene, with alleles for black and orange-brown, so XBXB and XBY cats will have a black coat, while XOXO and XOY will have an orange-brown coat. Another possible combination for female cats would be XBXO. Both of the color alleles would be expressed, so the cat would end up being partially brown and partially black.
Origin of Calico Coat As mentioned, during embryonic development, one X, at random, turns off in each cell in a female’s body. For a cat who is XBXB or XOXO, since both Xs are the same, this won’t be noticed, but if a female is XBXO, in some of her cells the XB will be turned off while in others, the XO will be turned off. As these cells multiply by mitosis, this will lead to patches of skin where black hair will be produced, while other patches will produce orange-brown fur. She will end up with the patchy coat color typical of calico or tortoiseshell cats. There is a similar, X-linked gene in human females for the presence of sweat glands in the skin. A woman who is heterozygous for this gene will have patchy skin containing some areas with and some without sweat glands. This discussion will hopefully lead you to think of several “what-if” questions:
But, . . . What Is “Sex,” Anyway?
We’ve been referring, here, to an organism with XX chromosomes as “female” and with XY chromosomes as “male,” but technically, that’s not really right. Sex is not a genotype, and it’s not right to assume that the mere presence of XX or XY determines an organism’s sex. Rather, sex is a phenotype that is dependent upon how a number of genes/alleles are expressed and interact with each other. In humans, there is a gene on the Y chromosome that codes for the presence and development of testes, and if those testes are formed, then, under guidance from other genes, they will begin to produce testosterone and other hormones that, in turn, are able to stimulate development of male genitalia. (Beard quality, by the way, is a totally separate, autosomal trait with its own genes/alleles, and its expression/phenotype is influenced by a variety of factors.) However, for development of male genitalia to happen, another gene, which is located on the X chromosome and which codes for the presence and functioning of testosterone receptors, must also do so. Interestingly, in human embryonic development, development of female genitalia is the “default” condition, so if there is no Y chromosome, there are no instructions to form testes and the baby develops as a girl, but even if there are testes and testosterone, and there’s also an alternate allele that codes for “faulty” or missing testosterone receptors, the baby still developes as a girl. Thus, the mere condition of being, chromosomally, XY, does not automatically mean that person is male! Again, sex is a phenotype, not a genotype. As described below, while it is not a very common thing, it is entirely possible that someone could have an X and a Y chromosome, yet because of the ways in which her alleles/genes are expressed, be phenotypically, female. In the past, before people knew about and were able to test for X and Y chromosomes, such a woman might have been labeled as “barren” or “infertile” – a bad-enough label, but now that we know about X and Y chromosomes and can test for their presence, some people, including some doctors and researchers, forgetting that sex is a phenotype, not a genotype, much less a karyotype, incorrectly and callously try to label these women as “chromosomally male” – a term which is sheer nonsense.
The “opposite” condition is also possible. A colleague told me of a case in which a couple who were having problems conceiving a baby went to a fertility specialist, and it was discovered that the very masculine, fully-bearded husband wasn’t producing sperm because he happened to be XX. Also, sex determination works differently in different species of animals. In humans and other mammals, due to the presence of Barr bodies, the expression of the genes/alleles on the Y chromosome “normally” results in a male phenotype, and thus people who are XXY (Klinefelter’s syndrome) are “normally” male. In comparison, in fruit flies, genes for some sexual traits are located on the autosomes and the ratio of the number of X and Y chromosomes determines the sex of the fly, so while an XY fly is normally male, an XXY fly typically is female. In grasshoppers, there is no Y chromosome, so a grasshopper with one X chromosome (symbolized as XO) is normally male, while a grasshopper with two X chromosomes (XX) is normally female. In birds and butterflies, sex determination works the “opposite” of mammals, so rather than confusing things by using X and Y to represent their sex chromosomes, typically the letters Z and W are used. Thus a male bird or butterfly typically has ZZ sex chromosomes, while a female typically has ZW. In bees and ants, there are no sex chromosomes, and diploid individuals typically show the female phenotype, while haploid individuals typically show the male phenotype. Thus while the mode of sex determination varies among different groups of animals (and plants), it is still true for all of them that sex is a phenotype, and that maleness or femaleness depends on the outcome of how that organism’s genes/alleles are expressed.
Androgen Insensitivity Syndrome (AIS) — A Sex-Linked Gene that Helps to Determine Sex
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