Lecture Summaries

1 Introduction and course overview During our first meeting, we will spend some time getting to know each other. The instructor will present a general overview of X chromosome biology along with the key concepts to be covered in the course. The format of the course, course assignments, course Web site, how to find scientific literature (PubMed search) and the preparation that will be expected of each student each week will also be discussed.
2 X chromosome genetics: Flies were first on the scene In the earliest years of the twentieth century, a founding generation of geneticists focused on problems of genetic transmission. Many exploited the fruit fly to answer classic questions such as, how are genes inherited? The X chromosome played a crucial role in numerous early seminal discoveries in genetics including the findings that genes are on chromosomes (Thomas Hunt Morgan), chromosomes are the structures of inheritance (Calvin Bridges), and genes are present in a linear array on chromosomes and can be ordered into a genetic map (Alfred Sturtevant). We will cover the 1st and 3rd of these three ground breaking discoveries and how they opened the door to a wealth of genetics experiments.
3 Medical diseases: Sex reversal and the X Genetic maps, as with the previously discussed fly X-linked map, have played an important role in the discovery of medical diseases. Use of pedigrees and genetic maps have helped map over 300 diseases to the X chromosome, including such classic examples as hemophilia and muscular dystrophy. Other traits such as colorblindness, which affects ~4% of all men, also map to the X chromosome. Men have a single X chromosome and a single Y chromosome (XY), while women have two X chromosomes (XX). X-linked diseases thus affect men more frequently than women, because in men a defect in an X-linked gene will be expressed, while in women the second X chromosome generally compensates for an X-linked defect. We will discuss two papers that utilized human genetic mapping to identify X-linked mutations that cause sex reversal leading to XX males (first paper) and XY females (second paper).
4 Dosage compensation I: X-inactivation in mammals Females have two X chromosomes and males have one, yet the levels of X chromosome gene expression are generally the same in the two sexes. How is this balance established? In mammals, females equalize the levels of X-linked gene expression by randomly silencing one of their two X chromosomes, so that a single X chromosome is active in females, as is the case in males (Paper #1). If a single X chromosome is active in each cell in both sexes, then is the level of X-linked gene expression doubled so X-linked gene expression is similar to autosomal levels, or does it remain half the level of autosomes? The second paper addresses this question.
5 Dosage compensation II: X-ceptions Random X-inactivation affects most genes in mammals. For example, the coat color gene for cats is located on the X chromosome. Since the silencing of the X chromosome is random during development, a female XX cat carrying alleles for orange and black coat color has patches of orange and patches of black, resulting in the calico cat phenotype. This week we will examine some exceptions to random X-inactivation. The first paper discusses some genes on the inactive X chromosome that escape X-inactivation and how these "escapees" help explain the steps by which dosage compensation evolved on the X chromosome. The second paper addresses an ongoing debate in the field of whether there is preferential inactivation of the paternal or maternal X chromosome in early embryonic development.
6 Dosage compensation III: Doubling and spreading Unlike in humans, in flies dosage compensation is regulated by doubling the level of X-linked transcription in XY males. A large complex, the dosage compensation complex, in males interacts with the X chromosome and up-regulates gene expression. We will examine how one of the key genetic regulators of sex determination in flies, sex-lethal, also regulates a member of the dosage compensation complex (Paper #1). We will then study how non-coding RNAs play an important role in "spreading" the dosage compensation complex along the X chromosome (Paper #2).
7 Dosage compensation IV: Half and half in worms Dosage compensation in worms is regulated by halving the level of X-linked transcription in XX hermaphrodites. The first paper establishes the presence of dosage compensation in worms and the identity of three genes involved in equalizing X-linked gene expression. These three genes have subsequently been shown to be critical components of the dosage compensation complex. Similar to flies, chromosome "spreading" of the dosage compensation complex also occurs in worms (Paper #2). We will discuss similarities and differences among the mechanisms of mammalian, fly and worm dosage compensation during this class.
8 A highly conserved chromosome The evolution of dosage compensation has consequences for the evolution of sex chromosome gene content. Susumu Ohno predicted that once a region of the X chromosome has evolved dosage compensation, then large genomic rearrangements (translocations) of the X chromosome with autosomes will be suppressed. Translocations would be suppressed because any autosomal region that moves to the X chromosome would not be dosage compensated. The suppression of translocations between the X chromosome and autosomes predicts that the X chromosome across all mammals should be highly conserved. This idea has been termed "Ohno's Law." The first paper examines the complete gene content of the human X chromosome and shows that Ohno's Law does indeed act throughout mammals. The second paper shows that the mammalian X chromosome is not completely "immutable" and that there has been rampant gene transposition to and from the X chromosome throughout mammalian evolution. The gene transposition rate from the X chromosome to autosomes far exceeds the rate of autosome to X or autosome to autosome gene transposition. We will discuss the theory behind why gene transposition rates from the X chromosome to autosomes are so high.
9 Gene content: A "sexy" X Do X chromosomes have a disproportionate number of genes that function in sex-specific biological processes? Evolutionary theory predicts that selection will enrich for alleles beneficial to males on the X chromosome. This appears to be the case for mammalian spermatogonially expressed genes (Paper #1). However, it is not the case for worms and flies (Paper #2), in which there is a paucity of genes on the X chromosome that exhibit male-specific expression.
10 Divergence of the X and Y chromosomes Around 300 million years ago the mammalian X and Y chromosomes were probably a normal pair of autosomes. Since then, the mammalian X chromosome has remained relatively intact by retaining most of its ~1000 genes. The human Y chromosome, on the other hand, has degenerated, with only ~70 genes remaining. The first paper proposes how this degeneration may have occurred by comparing the genetic divergence between Y-linked genes and their ancestral X-linked counterparts. The second paper looks more deeply into the mammalian evolutionary tree by examining the platypus (a monotreme), which has 5 X chromosomes and 5 Y chromosomes.
11 Hybrids I: Haldane's rule Haldane's Rule refers to the fact that when species hybrids are formed, it is typically the heterogametic sex (XY or ZW) that is either sterile or inviable. The homogametic sex is typically fertile. Amazingly, Haldane's Rule holds across a wide range of XY (mammals and Drosophila) and ZW (birds and butterflies) organisms. What are the genetic factors that drive hybrid sterility in XY males? This class will focus on two papers that use Drosophila genetics to identify individual regions and genes responsible for hybrid male sterility. Both studies show that the X chromosome is a hub for genes involved in hybrid male sterility.
12 Hybrids II: Are hybrids a step in the formulation of new species? One of the classic genetic cases of mammalian hybrids is the European mouse hybrid zone that separates two distinct mouse species, Mus musculus and Mus domesticus. In this zone, hybrid males that form between these two species are sterile. The first paper maps a region on the X chromosome involved in hybrid male sterility and studies the phenotypic characterization of these hybrid sterile mice. In animals, much of the work on hybrids has focused on identifying the genes involved in hybrid sterility or hybrid inviability. However, as is well known in plants, hybridization can also give rise to new species. There are a few cases of hybrid speciation in animals, but it is currently unclear how frequently animal hybrid speciation occurs. With the accumulation of massive amounts of sequence data from numerous species, one can look at the DNA sequence level for genetic signatures of hybrid speciation. The second paper addresses what such genetic signatures of hybrid speciation may be and proposes a controversial view that humans arose via a hybrid speciation event with chimpanzees.
13 Student presentations/course summary During this last class we will have the student oral presentations. We will also discuss the articles covered in this course and what lies ahead in the world of X chromosome biology.