This is Old Lecture 9
Text Assignment: Chapter 4, pages 100-114. These pages include all chapter end problems.
Important terms to learn
X and Y chromosomes: For dioecious species (those in which each sex is in a separate individual), there are usually chromosomal differences between male and female. The pattern in humans and most mammals and in Drosophila is that the females have two homologous chromosomes (called X chromosomes), while the males have only one X chromosome, paired with a much smaller Y chromosome that carries relatively little genetic information.
Homogametic and heterogametic: In the XX/XY sex chromosome system, the female is referred to as the homogametic sex because she has two homologous sex chromosomes. The male is such species is called heterogametic because he has non-homologous sex chromosomes. However, there is a small "pseudoatosomal" region of homology that pairs during the meiotic prophase to allow X and Y chromosomes to be distributed systematically, such that each gamete normally carries one X or one Y chromosome.
Patterns of inheritance: In this lecture, we will focus primarily on patterns of inheritance in the XX/XY system in mammals, including humans, and in Drosophila, with some brief references to other systems. As discussed in the previous lecture, the mechanisms of sex determination and the mechanisms of dosage compensation are both quite different in Drosophila than in typical mammals, including humans. However, despite these mechanistic differences, their patterns of sex-linked inheritance are quite similar.
XY males are hemizygous: One of the features of an X/Y sex chromosome system is that females have two copies of the X chromosome, one of which is inherited from each parent, whereas males have only one, inherited from the mother, and paired with a Y chromosome inherited from the father. Because there is only one X in males, any recessive alleles that it carries are fully expressed in a manner comparable to that seen in a homozygous recessive female. Males are therefore described as being hemizygous for genes carried on the X chromosome.
Drosophila white-eyed mutation: The first definitive data linking genes to chromosomes (published in 1910 by Thomas Hunt Morgan) came from studies of the white-eyed mutation in Drosophila (see pages 100-101 of the text). When a white-eyed male was crossed with a wild-type female, all F1 progeny were phenotypically wild-type. However, half of the F2 males were white-eyed, whereas all of the females were phenotypically wild-type (Fig 4.16, Cross A).
X chromosome linkage: Phenotypic expression of the white-eyed mutation in F2 males was thus directly associated with the X chromosome that had been passed from the white-eyed parental male to the phenotypically wild type F1 females and then to one-half of their F2 male progeny, where the recessive mutation was expressed because of the hemizygous nature of the male X chromosome. Because all of the F1 males had received a wild-type X chromosome from their wild-type female parent, all of the F2 females received a wild-type eye color allele from their fathers, and were thus phenotypically wild-type irrespective of which allele they received from their heterozygous mothers.
Homozygous white-eyed females: White-eyed females were obtained only in crosses that allowed them to inherit an X chromosome carrying the recessive white-eyed allele from each parent (for example, in a cross of a heterozygous F1 female with a white-eyed male). When a white eyed female was mated with a wild-type male, all of the male progeny were white-eyed and all of the female progeny were red eyed (Fig 4.16, cross B). The F2 generation (white eyed male crossed to heterozygous female) yielded half red eyes and half white eyes in both sexes. The hemizygous males inherited either red or white from their heterozygous mothers, and the females received either a red or a white from their mothers, always paired with a white from their fathers.
Significance: At the time of its discovery in 1910, sex linkage was the first direct experimental confirmation that inheritance was associated with specific chromosomes. This had been suspected since the discovery of the behaviour of chromosomes in meiosis a few years earlier, but no direct link had previously been forged between a physical entity and the inheritance of a specific trait. Similar results were also obtained in the original studies with two other X-linked genes, miniature wing and yellow body. In addition to verifying the chromosomal theory of inheritance, these studies also provided the basis for many new experimental approaches. We have already seen the use of two X-linked markers, white eyes and miniature wings, to verify the chromosomal mechanisms involved in the formation of a gynandromorph (textbook figure 9.8). In the next lecture, we will see that the first studies on genetic recombination and map distances were done with genetic loci that had already been demonstrated to be carried on the Drosophila X-chromosome. (Chapter 5, pages 119-120).
Crisscross pattern of inheritance: The original excitement over the linking of heredity to chromosomes has long since been supplanted by more recent studies showing that DNA is the genetic material and that genetic information is coded into the DNA nucleotide sequence. Thus, for the modern student of genetics, the significance of X-linkage is more likely to be the modification that it imposes on Mendelian patterns of inheritance. In particular, there is a crisscross pattern of inheritance, in which a recessive allele that is expressed in a male is transmitted only to daughters (who usually fail to express the phenotype unless their mothers were also carriers of the same recessive allele), and then from those daughters to half of their sons, who exhibit a hemizygous recessive phenotype identical to that of their grandfather. Another characteristic feature of X-linkage is that homozygous recessive mothers pass X-linked traits to all of their sons, whereas none of their daughters may be phenotypically affected (provided that the father is not affected).
Sex linkage in humans: Many human diseases, disorders and phenotypic traits have been show to be inherited as alleles carried on the X chromosome. A number of such conditions are summarized in Table 4.5 in the textbook, and several are discussed briefly below. In addition, both in humans and in other species, there are numerous traits that are not X-linked whose phenotypic expression is limited or influenced by hormonal mechanisms related to sexual differentiation. These will be discussed separately in a later section of this lecture.
Color blindness: Half of the sons of a woman who is heterozygous for color blindness will be color blind, irrespective of the genotype of their father. If the father is color blind, half of the daughters will also be color blind. If the father has normal vision, none of the daughters will be color blind. A normal vision man and a normal vision woman who is heterozygous for color blindness will produce progeny with a 3:1 ratio of normal vision to color blind, but all of the color blindness will be in male progeny. Note that all of this is an oversimplification. There are actually various types of color blindness involving loss of sensitivity to different colors of light.
Hemophilia: This disorder of blood clotting is X-linked and is common in the males of European royal families because of frequent consanguineous matings within this limited breeding pool. Pedigrees suggest that Queen Victoria of England was heterozygous for classic hemophilia (hemophilia A), which involves a deficiency of clotting factor VIII. Hemophilia B, with a deficiency of clotting factor IX, is also X-linked (Table 4.5).
Lesch-Nyhan Syndrome: This X-linked disease involves an absence of the enzyme hypoxanthine-guanine phosphoribosyl transferase (HGPRT), which is involved in a so-called "salvage" pathway for utilization of purine bases that have become available either from dietary sources (nearly all foods contain some amount of nucleic acids) or as the result of recycling processes within the body. Loss of HGPRT results in severe mental retardation and a strange self-mutilating syndrome. Because victims of this disease die young without reproducing, it is seen primarily in males.
Selective growth of HGPRT positive cells: Cultured cells that lack HGPRT are unable to multiply when de novo synthesis of purines is blocked with aminopterin or similar drugs. This trait can be used to select for cells that have acquired a functional HGPRT gene by incorporation of a plasmid or fusion with another cell type that contains a functional gene. Such cells gain the ability to utilize preformed purines and thus can be selected for on the basis of their ability to multiply when provided with purines in the presence of aminopterin.
Duchenne muscular dystrophy: This is another genetic disease that is rare in females because affected males do not live long enough to reproduce. The defect is in a very large protein that is coded for from a huge locus consisting of over 2 million base pairs. The large size of the locus, as well as some of its structural features result in a high rate of new mutation. The relatively high frequency of this genetic disease appears to be sustained almost entirely by that high rate of mutation.
Y-linked inheritance: This is rare except for maleness, because females would not express the traits. Even maleness is only Y-linked for the first step in a regulatory hierarchy. One possible human Y-linked trait is hairy rims of ears. There are also some non-functional pseudogenes in one of the pseudoautosomal regions of the human Y chromosome (those regions that pair with the X chromosome during meiosis. The pseudoautosomal region in Drosophila contains a few functional genes.
X-linked dominant genes: These are expressed in males and all of their daughters, but not in their sons (unless the mother of the sons also expresses the trait). Half of the sons and half of the daughters of a heterozygous woman and an unaffected man will be affected. Overall, more females than males are affected. One example in humans is an X-linked gene that causes defective dentine of the teeth.
Sex linkage in ZZ/WZ systems: Our textbook chooses (perhaps wisely) not to get into patterns of sex linked inheritance in species such as chickens, where the male is homogametic (ZZ) and the female is heterogametic (WZ). The principles are the same as for XX/XY species, except that the patterns are reversed with regard to sex. The female exhibits hemizygous expression of genes carried on the Z chromosome that are recessive to wild type in the homogametic male. Although we are not going to pursue such patterns in any of our exercises or review questions, you need to be aware that they exist.
Sex-limited traits: These are traits that are not genetically sex-linked, but are only expressed in one sex, mostly because of hormonal controls. The textbook focuses on the differences in shapes of feathers in hens and roosters (Fig. 4.19). Whether or not the males in particular strains of chickens express the pattern known as cock feathering is determined by alleles at an autosomal locus. The pattern that we commonly associate with roosters is actually a recessive autosomal trait (which has obviously been selected by chicken breeders). A rooster with the dominant phenotype exhibits a pattern of feathering that is not different from that of hens. However, the recessive (hh) cock feathering phenotype occurs only in males. Females of the same genotype still express typical hen feathers.
Human sex-limited traits: It is probably reasonably safe to cite facial hair in men and breast development in women as examples of sex-limited traits. Both of these phenomena are under the control of hormones that are relatively gender-specific. However, individuals of both sexes normally express low levels of the hormones associated primarily with the other sex, and cases can be found within the usually accepted range of normalcy where there is some degree of expression of facial hair in women or breast enlargement in men. Thus, one can argue that these traits are actually sex-influenced, rather than strictly sex-limited.
Sex-influenced traits: These traits are expressed to some degree in both sexes, but are differentially affected by sex hormones. Examples include amount of body hair, muscle mass, and male pattern balding. In the case of pattern balding, there is an autosomal gene pair that determines a propensity to the condition. The amount of thinning of the hair or balding that is observed depends both on genotype and the amount of testosterone exposure. The relationship is presented in a small table on page 104, which must be combined with the text to gain a full understanding. A male who is BB will show severe balding. A female who is BB will also be affected, but later in life and usually less severely, with a thinning of the hair, rather than total loss. A male who is heterozygous (Bb) will also become bald, whereas a female who is heterozygous will not be affected. Individuals of either sex who are fully recessive (bb) will not be affected.
Purebred dogs: Although not directly related to the rest
of this lecture, pages 104 and 105 contain a boxed discussion
of the genetic problems that have been accumulated as a result
of inbreeding in various lines of purebred dogs. There
is a special risk of increasing the relative frequency of rare
recessive alleles in a population through the mating of closely
related individuals. We will explore the mathematical basis for
this risk in the section on population genetics near the end of
the semester. If you wish to look ahead, the major discussion
of this topic is on pages 673-676.